3-azabicyclo[3.1.0]hexane derivatives useful in therapy

ABSTRACT

Compounds of formula (I), their salts and prodrugs thereof, where the substituents are as defined herein are disclosed as opiate binding agents useful in the treatment of opiate-mediated conditions. Also described are processes for making such substances.

[0001] This invention relates to pharmaceutically useful compounds, inparticular compounds that bind to opiate receptors (e.g. mu, kappa anddelta opioid receptors). Compounds that bind to such receptors arelikely to be useful in the treatment of diseases modulated by opiatereceptors, for example irritable bowel syndrome; constipation; nausea;vomiting; and pruritic dermatoses, such as allergic dermatitis and atopyin animals and humans. Compounds that bind to opiate receptors have alsobeen indicated in the treatment of eating disorders, opiate overdoses,depression, smoking and alcohol addiction, sexual dysfunction, shock,stroke, spinal damage and head trauma.

[0002] There is a particular need for an improved treatment of itching.Itching, or pruritus, is a common dermatological symptom that can giverise to considerable distress in both humans and animals. Pruritus isoften associated with inflammatory skin diseases which may be caused byhypersensitivity reactions, including reactions to insect bites, such asflea bites, and to environmental allergens, such as house dust mite orpollen; by bacterial and fungal infections of the skin; or byectoparasite infections.

[0003] Existing treatments that have been employed in the treatment ofpruritus include the use of corticosteroids and antihistamines. However,both of these treatments are known to have undesirable side effects.Other therapies that have been employed include the use of essentialfatty acid dietary supplements, though these have the disadvantages ofbeing slow to act, and of offering only limited efficacy againstallergic dermatitis. A variety of emollients such as soft paraffin,glycerine and lanolin are also employed, but with limited success.

[0004] Thus, there is a continuing need for alternative and/or improvedtreatments of pruritus.

[0005] Certain 4-arylpiperidine-based compounds are disclosed in interalia European patent applications EP 287339, EP 506468 and EP 506478 asopioid antagonists. In addition, International Patent Application WO95/15327 discloses azabicycloalkane derivatives useful as neurolepticagents.

[0006] According to the invention there is provided a compound offormula I,

[0007] wherein

[0008] the “Ar” ring represents an optionally benzo-fused phenyl or 5-or 6-membered heteroaryl ring;

[0009] R¹ when taken alone is H, halogen, NO₂, NH₂, NY²WY¹, Het¹, AD,CO₂R⁷, C(O)R⁸, C(═NOH)R⁸, or OE,

[0010] Y² is H, C₁₋₆ alkyl, C₃₋₆ alkenyl (each of which alkyl andalkenyl is optionally substituted by aryl, aryloxy or Het¹),

[0011] W is SO₂, CO, C(O)O, P(Y¹)═O, P(Y¹)═S,

[0012] Y¹ is C₁₋₁₀ alkyl (optionally substituted by one or moresubstituents independently selected from halogen, OH, C₁₋₄ alkoxy, C₁₋₆alkanoyloxy, CONH₂, C₁₋₆ alkoxycarbonyl, NH₂, aryl, mono- or di(C₁₋₄alkyl)amino, C₃₋₈ cycloalkyl, phthalimidyl, Het¹), Het¹, aryl(optionally substituted by one or more substituents independentlyselected from C₁₋₄ alkyl, C₁₋₄ haloalkyl and halogen), NH₂, N(C₁₋₆alkyl)₂ or NH(C₁₋₆ alkyl),

[0013] Het¹ is a heterocyclic group containing up to 4 heteroatomsselected from N, O and S, which may comprise up to 3 rings (preferably aheteroaryl group, optionally benzo- or pyrido-fused heteroaryl),optionally substituted by one or more substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkyl, C₁₋₆ haloalkoxy,C₃₋₆ haloalkyl, C₃₋₆ halocycloalkyl, ═O, OH, halogen, NO₂,SiR^(19a)R^(19b)R^(19c), CON^(20a)R^(20b), NR^(20a)R^(20b), SR^(21a),NR^(21b)SO₂R^(22a), NR^(21c)C(O)OR^(22b), NR^(21d)COR^(22d), and C₁₋₆alkoxycarbonyl, and if a S atom is present in a ring, it can be presentas part of a —S—, S(O)— or —S(O₂)— group, and carbon atoms in the ringcan be present as a part of a carbonyl moiety;

[0014] R^(19a), R^(19b), R^(19c) each independently representC_(1-6b)alkyl or aryl,

[0015] R^(20a) and R^(20b) each independently represent H,C_(1-6b)alkyl, aryl, (C₁₋₄ alkyl)phenyl, each of which alkyl, aryl andalkylphenyl are optionally substituted by one or more C₁₋₄ alkyl, C₁₋₄alkoxy, OH, NO₂, NH₂ and/or halogen,

[0016] or R^(20a) and R^(20b) can be taken together with the N atom towhich they are attached, to form a 4- to 6-membered ring optionallysubstituted by one or more substitutuents independently selected fromone or more C₁₋₄ alkyl, C₁₋₄ alkoxy, OH, ═O, NO₂, NH₂ and/or halogen,

[0017] R^(21a, b, c) and ^(d) each independently represent H, C₁₋₆alkyl, aryl or C₁₋₄ alkylphenyl, each of which alkyl, aryl, andalkylphenyl are optionally substituted by one or more C₁₋₄ alkyl, C₁₋₄alkoxy, OH, NO₂, halogen, NH₂,

[0018] R^(22a, b) and ^(c) each independently represent C₁₋₆ alkyl, arylor C₁₋₄ alkylphenyl, each of which alkyl, aryl, and alkylphenyl areoptionally substituted by one or more C₁₋₄ alkyl, C₁₋₄ alkoxy, OH, NO₂,halogen, NH₂,

[0019] A is C₁₋₄ alkylene, C₂₋₄ alkenylene or C₂₋₄ alkynylene, each ofwhich is optionally substituted by one or more C₁₋₄ alkyl, C₁₋₄ alkoxy,halogen and/or OH,

[0020] D is H, OH, CN, NR²⁵R²⁶, CONR²⁵R²⁶, NHR²⁷, CO₂R²⁸, COR²⁹,C(═NOR)R²⁹,

[0021] or AD is CN, NR²⁵R²⁶, CONR²⁵R²⁶,

[0022] where R²⁵ and R²⁶ are either each independently H, C₁₋₃ alkyl,C₃₋₈ cycloalkyl, aryl, C₁₋₄ alkylphenyl (each of which C₁₋₃ alkyl, C₃₋₈cycloalkyl, aryl and C₁₋₄ alkylphenyl are optionally substituted by oneor more NO₂, halogen, C₁₋₄ alkyl and/or C₁₋₄ alkoxy, (each of whichlatter C₁₋₄ alkyl and C₁₋₄ alkoxy is optionally substituted by one ormore halogen)),

[0023] or R²⁵ and R²⁶ are taken together with the N atom to which theyare attached and can form a 4- to 7-membered heterocyclic ringoptionally incorporating one or more further hetero atoms selected fromN, O and S, and which ring is optionally substituted by one or more C₁₋₄alkyl, OH, ═O, NO₂, NH₂and/or halogen,

[0024] R²⁷ is COR³⁰, CO₂R^(31a), SO₂R^(31b),

[0025] R²⁸ and R²⁹ are each independently H, C₁₋₆ alkyl, C₃₋₈cycloalkyl, aryl or C₁₋₄alkylphenyl, each of which C₁₋₆ alkyl, C₃₋₈cycloalkyl, aryl and C₁₋₄ alkylphenyl are optionally substituted by oneor more NO₂, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy (each of which latter C₁₋₄alkyl and C₁₋₄ alkoxy are optionally substituted by one or morehalogen),

[0026] R³⁰ is H, C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, C₃₋₈cycloalkyloxy, aryl, aryloxy, C₁₋₄ alkylphenyl, phenyl(C₁₋₄)alkoxy,(each of which C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, C₃₋₈cycloalkyloxy, aryl, aryloxy, C₁₋₄ alkylphenyl and phenyl(C₁₋₄)alkoxyare optionally substituted by one or more NO₂, halogen, C₁₋₄ alkyl, C₁₋₄alkoxy (which latter alkyl and alkoxy are optionally substituted by oneor more halogen)),

[0027] R^(31a) and R^(31b) are each independently C₁₋₄ alkyl, C₃₋₈cycloalkyl, aryl or C₁₋₄ alkylphenyl, each of which is optionallysubstituted by one or more NO₂, halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy, eachof which latter alkyl and alkoxy is optionally substituted by one morehalogen

[0028] E is H, CONR³²R³³, CSNR³²R³³, COR³⁴, CO₂R³⁴, COCH(R^(34a))NH₂,R³⁵, CH₂CO₂R^(35a), CHR^(35b)CO₂R^(35a), CH₂OCO₂R^(35c),CHR^(35d)OCO₂R^(35c), COCR³⁶═CR³⁷NH₂, COCHR³⁶CHR³⁷NH₂, or PO(OR³⁸)₂,

[0029] R³² and R³³ are each independently H, C₃₋₁₀ alkylalkenyl, C₃₋₇cycloalkyl (optionally substituted by C₁₋₄ alkyl), phenyl (optionallysubstituted by (X)_(n)), C₁₋₁₀ alkyl (optionally substituted by C₄₋₇cycloalkyl (optionally substituted by C₁₋₄ alkyl) or phenyl optionallysubstituted by (X)_(n)),

[0030] or R³² and R³³ can be taken together with the N atom to whichthey are attached and can form a 5- to 8-membered heterocycle optionallycomprising further hetero atoms selected from N, O and S, whichheterocycle is optionally substituted by C₁₋₄ alkyl, optionallysubstituted by one or more halogen,

[0031] R³⁴ is H, C₄₋₇ cycloalkyl (optionally substituted by one or moreC₁₋₄ alkyl), phenyl (optionally substituted by (X)_(n), C₁₋₄alkanoyloxy, NR³²R³³, CONR³²R³³ and/or OH), or C₁₋₆ alkyl (optionallysubstituted by one or more halogen, C₄₋₇ cycloalkyl (optionallysubstituted by one or more C₁₋₄ alkyl), or phenyl (optionallysubstituted by (X)_(n), C₁₋₄ alkanoyloxy, NR³²R³³, CONR³²R³³ and/or OH))

[0032] R^(34a) is H, C₁₋₆ alkyl (optionally substituted by one or morehalogen, C₄₋₇ cycloalkyl (optionally substituted by one or more C₁₋₄alkyl), or phenyl (optionally substituted by (X)_(n), C₁₋₄ alkanoyloxy,NR³²R³³, CONR³²R³³ and/or OH)), C₄₋₇ cycloalkyl (optionally substitutedby one or more C₁₋₄ alkyl), phenyl (optionally substituted by (X)_(n),C₁₋₄ alkanoyloxy, NR³²R³³, CONR³²R³³ and/or OH) or a naturally occuringamino acid substituent,

[0033] R³⁵ is C₄₋₇ cycloalkyl optionally substituted by one or more C₁₋₄alkyl, phenyl (optionally substituted by one or more (X)_(n), C₁₋₄alkanoyl, NHR³², CON(R³²)₂, and/or OH), C₁₋₆ alkyl (optionallysubstituted by C₄₋₇ cycloalkyl optionally substituted by one or moreC₁₋₄ alkyl, or phenyl (optionally substituted by one or more (X)_(n),C₁₋₄ alkanoyl, NHR³², CON(R³²)₂, and/or OH)), C₁₋₄ alkoxy(C₁₋₄ alkyl),phenyl(C₁₋₄)alkyloxy(C₁₋₄)alkyl, tetrahydropyranyl, tetrahydrofuranyl,cinnamyl or trimethylsilyl,

[0034] R^(35a, b, c) and ^(d) are each independently H, C₄₋₇ cycloalkyloptionally substituted by one or more C₁₋₄ alkyl, phenyl optionallysubstituted by one or more (X)_(n) or C₁₋₆ alkyl (optionally substitutedby C₄₋₇ cycloalkyl optionally substituted by one or more C₁₋₄ alkyl, orphenyl optionally substituted by one or more (X)_(n)),

[0035] R³⁶ and R³⁷ each independently represent H, C₃₋₆ alkylalkenyl,C₄₋₇ cycloalkyl, phenyl optionally substituted by one or more (X)_(n),or C₁₋₆ alkyl (optionally substituted by C₄₋₇ cycloalkyl optionallysubstituted by one or more C₁₋₄ alkyl, or phenyl optionally substitutedby one or more (X)_(n)),

[0036] R³⁸ is C₄₋₇ cycloalkyl optionally substituted by one or more C₁₋₄alkyl, phenyl optionally substituted by one or more (X)_(n), or C₁₋₆alkyl (optionally substituted by C₄₋₇ cycloalkyl optionally substitutedby one or more C₁₋₄ alkyl, or phenyl optionally substituted by one ormore (X)_(n)),

[0037] R² when taken alone is H or halogen;

[0038] or R¹ and R², when attached to adjacent carbon atoms, can betaken together with the carbon atoms to which they are attached, and mayrepresent Het^(1a);

[0039] Het^(1a) is a heterocyclic group containing up to 4 heteroatomsselected from N, O and S, which may comprise up to 3 rings (and ispreferably an optionally benzo-fused 5- to 7-membered heterocyclic ring)and which group is optionally substituted by one or more substituentsindependently selected from OH, ═O, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy and C₁₋₄ haloalkoxy, which C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy and C₁₋₄ haloalkoxy groups can be optionally substituted by oneor more C₃₋₆ cycloalkyl, aryl(C₁₋₆)alkyl, which aryl group is optionallysubstituted by one or more halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy and C₁₋₄ haloalkoxy, which latter C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy and C₁₋₄ haloalkoxy groups can be optionally substituted byone or more NR²³R²⁴, NR²³S(O)_(n)R²⁴, NR²³C(O)_(m)R²⁴, and if a S atomis present in a ring, it can be present as part of a —S—, S(O)— or—S(O₂)— group,

[0040] which R²³ and R²⁴ when taken alone independently represent H,C₁₋₄ alkyl, or C₁₋₄ haloalkyl,

[0041] or R²³ and R²⁴ can be taken together with the N atom to whichthey are attached, to form a 4 to 6-membered heterocyclic ringoptionally comprising one or more further heteroatoms selected from, N,O, or S, and which heterocyclic ring is optionally substituted by one ormore halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy and/or C₁₋₄haloalkoxy groups,

[0042] R³ is H, CN, halogen, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₂₋₆alkanoyl, C₂₋₆ alkanoyloxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyloxy, C₄₋₉cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle,NR¹²R¹³, CONR¹²R¹³, NY²WY¹, C₁₋₆ alkyl C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,(each of which alkyl, alkenyl and alkynyl groups is optionallysubstituted by one or more CN, halogen, OH, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, C₂₋₆ alkyloxycarbonyloxy, C₁₋₆ alkanoyl, C₁₋₆alkanoyloxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyloxy, C₄₋₉ cycloalkanoyl,aryl, aryloxy, heteroaryl, saturated heterocycle, N¹²R¹³, CONR¹²R¹³and/or NY²WY¹),

[0043] R⁴ is C₁₋₁₀ alkyl, C₃₋₁₀ alkenyl or C₃₋₁₀ alkynyl each of whichgroups is linked to the N atom via a sp³ carbon, and which is optionallysubstituted by one or more OH, CN, halogen, C₁₋₆ alkoxy (optionallysubstituted by aryl), aryloxy (optionally substituted by one or morehalogen, C₁₋₆ alkyl(optionally substituted by one or more CN and/orhalogen), C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, OH and/or NY²WY), C₁₋₆alkoxycarbonyl, C₂₋₆ alkanoyl, C₂₋₆ alkanoyloxy, C₃₋₈ cycloalkyl, C₃₋₈cycloalkyloxy, C₄₋₉ cycloalkanoyl, aryl (optionally substituted by oneor more halogen, C₁₋₆ alkyl(optionally substituted by one or more CNand/or halogen), C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, OH and/or NY²WY), C₁₋₄alkoxy, C₁₋₄ haloalkoxy, OH, C₁₋₄ haloalkoxy, and/or NY²WY), heterocycle(optionally benzo-fused and optionally substituted by one or morehalogen, C₁₋₆ alkyl(optionally substituted by one or more CN and/orhalogen), C₋₁₄ alkoxy, OH, C₁₋₄ haloalkoxy, and/or NY²WY),heterocyclyloxy (optionally substituted by one or more halogen, C₁₋₆alkyl(optionally substituted by one or more CN and/or halogen), C₁₋₄alkoxy, OH, C₁₋₄ haloalkoxy, and/or NY²WY), adamantyl or ZBNR¹⁴R¹⁵,

[0044] Z is a direct bond, CO or S(O)_(n) group,

[0045] B is (CH₂)_(p),

[0046] R¹² and R¹³ each independently represent H or C₁₋₄ alkyl,

[0047] or R¹² and R¹³ can be taken together with the N atom to whichthey are attached to form a 4- to 7membered heterocycle optionallycomprising a further hetero moiety selected from NR¹⁶, O and/or S, andwhich is optionally substituted by one or more C₁₋₄ alkyl,

[0048] R¹⁴ and R¹⁵ each independently represent H, C₁₋₁₀ alkyl, C₃₋₁₀alkenyl, C₃₋₁₀ alkynyl, C₃₋₈ cycloalkyl, aryl or heteroaryl,

[0049] or R¹⁴ and R¹⁵ can be taken together with the N atom to whichthey are attached to form a 4- to 7-membered heterocycle optionallycomprising a further hetero moiety selected from NR¹⁶, O and/or S, andwhich is optionally substituted by one or more C₁₋₄ alyl,

[0050] R¹⁶ is H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, (C₁₋₆ alkylene)(C₃₋₈cycloalkyl) or (C₁₋₆ alkylene)aryl,

[0051] R⁵ and R⁸ when taken separately are each independently H, C₁₋₆alkyl,

[0052] R⁵ and R⁸ when taken separately are each independently H, C₁₋₆alkyl,

[0053] R⁵ and R⁸ can be taken together with the carbon atoms to whichthey are joined to form a C₃₋₈ cycloalkyl ring,

[0054] R⁶, R⁷, R⁹ and R¹⁰ when taken separately are H,

[0055] R⁵ and R⁶ or R⁷ can be taken together with the carbon atoms towhich they are joined to form a C₃₋₈ cycloalkyl ring,

[0056] X is halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl or C₁₋₄haloalkoxy,

[0057] m is 1 or 2;

[0058] n is 0, 1 or 2;

[0059] p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0060] q is 0 or 1;

[0061] “Naturally occuring amino acid substituent” means theα-substituent that occurs in isoleucine, phenylalanine, tryptophan,tyrosine, histidine, serine, threonine, methionine, cysteine, asparticacid, glutamic acid, asparagine, glutamine, lysine, arginine or proline;

[0062] “Heteroaryl” represents an aromatic ring containing up to fourheteroatoms independently selected from N, O and S, and if a S atom ispresent in the ring, it can be present as part of a —S—, S(O)— or—S(O)₂— group, and which may be joined to the remainder of the compoundvia any available atom(s).

[0063] “Heterocycle” is a group containing 1, 2 or 3 rings, and whichcontains up to 4 ring heteroatoms selected from N, O and S and up to 18ring carbon atoms;

[0064] “Aryl”, including in the definitions of “aryloxy”, etc., means agroup comprising a ring and which may be joined to the remainder of thecompound via any available atom(s) (examples of such groups includenaphthyl, indanyl, etc.);

[0065] “Alkyl”, “alkenyl” and “alkynyl” groups can be linear or branchedif the number of carbon atoms allows;

[0066] “Cycloalkyl” groups can be polycyclic if the number of carbonatoms allows;

[0067] or a pharmaceutically or veterinarily acceptable derivative orprodrug thereof.

[0068] Where a fused heterocyclic group is present it can be attached tothe remainder of the compound via any available atom(s).

[0069] “Haloalkyl”, “haloalkoxy” groups and the like can contain morethan one halogen atoms, and for instance can be per-halogenated.

[0070] Certain of the compounds of the invention can exist in one ormore geometric and/or stereoisomeric forms. The present inventionincludes all such individual isomer and salts and prodrugs thereof.

[0071] Certain compounds of the present invention may exist in more thanone tautomeric form. Similarly certain compounds of the invention nayhave zwitterionic forms. It is to be understood that the inventionembraces all such tautomer, zwitterions and their derivatives.

[0072] The pharmaceutically acceptable salts of the compounds of theformula (I) include the acids which form non-toxic salts and examplesare the hydrochloride, hydrobromide, hydroiodide, sulphate, hydrogensulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate,fumarate, lactate, tartrate, citrate, gluconate, succinate, benzoate,methanesulphonate, benzenesulphonate and p-toluenesulphonate salts.Suitable base salts are formed from bases which form non-toxic salts andexamples are the aluminium, calcium, lithium, magnesium, potassium,sodium, zinc and diethanolamine salts. For a review on suitable saltssee Berge et al, J. Pharm. Sci., 66, 1-19 (1997).

[0073] It will be appreciated by those skilled in the art that certainprotected derivatives of not possess pharmacological activity as such,but may, in certain instances, be transformed after administration intoor onto the body, for example by metabolism, to form compounds offormula (I) which are pharmacologically active. Such derivatives areincluded in the term “prodrug”. It will further be appreciated by thoseskilled in the art that certain moieties known to those skilled in theart as “pro-moieties”, for example as described in “Design of Prodrugs”by H Bundgaard (Elsevier) 1985, may be placed on appropriatefunctionalities when such functionalities are present in compounds offormula (I), also to form a “prodrug”. Further, certain compounds offormula I may act as prodrugs of other compounds of formula I. Allprotected derivatives, and prodrugs, of the compounds of formula I areincluded within the scope of the invention.

[0074] Preferably the “Ar” ring represents phenyl or pyridyl.

[0075] Most preferably the “Ar” ring represents a group of formula:

[0076] Preferably R¹ when taken alone is OH, CN, halogen, NO₂, NH₂,NY²WY¹ or Het¹. More preferably R¹ when taken alone is OH, CN, I, Cl,NH₂, NO₂, optionally benzo-fused heteroaryl, NHSO₂Y¹, NHCOY¹ or NHCO₂Y¹.

[0077] Yet more preferably R¹ when taken alone is OH, CN, I, Cl, NH₂,NO₂,1,2,3-triazolyl, 1,2,4-triazolyl, imidazol-2-yl, pyridin-2-yl,thien-2-yl, imidazol-4-yl, benzimidazol-2-yl, NHSO₂(C₁₋₆ alkyl),NHSO₂(C₁₋₆ alkyl substituted by methoxy, CONH₂, OH, CO₂(C₂₋₆ alkyl),phthalimido, NH₂ or halogen), NHSO₂NH₂, NHSO₂NH(C₁₋₆ alkyl), NHSO₂N(C₁₋₆alkyl)₂, NHSO₂Het_(1a), NHCO(C₁₋₆ alkyl) or NHCO₂(C₁₋₆ alkyl). Even morepreferably R¹ is OH, NHSO₂CH₃, NHSO₂C₂H₅, NHSO₂(n-C₃H₇), NHSO₂(i-C₃H₇),NHSO₂(n-C₄H₇), NHSO₂NH(i-C₃H₇), NHSO₂(N-methylimidazol-4-yl),NHSO₂(CH₂)₂OCH₃, NHSO₂(CH₂)₂OH, 1,2,4-triazolyl or imidazol-2-yl. Mostpreferably R¹ is OH, NHSO₂CH₃, NHSO₂C₂H₅ or imidazol-2-yl.

[0078] Preferably R² when taken alone is H.

[0079] R¹ and R² when taken together with the carbon atoms to which theyare attached are preferably an optionally benzo-fused 5- to 7-memberedheteroaryl ring optionally substituted by C₁₋₄ alkyl or C₁₋₄ haloalkyl.

[0080] More preferably R¹ and R² when taken together with the carbonatoms to which they are attached are a 5-membered heteroaryl moietyoptionally substituted by C₁₋₄ alkyl or C₁₋₄ haloalkyl.

[0081] Yet more preferably R¹ and R² when taken together with the carbonatoms to which they are attached are an imidazole group optionally2-substituted by CF₃.

[0082] Preferably X is Cl.

[0083] Preferably n is 0.

[0084] Preferably q is 0.

[0085] Preferably R³ is H, CN, C₁₋₆ alkyl (optionally substituted by oneor more halogen, OH, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₂₋₆ alkanoyl,C₂₋₆ alkanoyloxy, C₂₋₆ alkyloxycarbonyloxy, NR¹²R¹³, CONR¹²R¹³ and/orNY²WY¹).

[0086] More preferably R³ is H, CH₃, C₂H₅, i-C₃H₇, n-C₃H₇ or CH₂OCH₃.

[0087] Most preferably R³ is CH₃.

[0088] Preferably R⁴ is C₁₋₁₀ alkyl, C₃₋₁₀ alkenyl or C₃₋₁₀ alkynyl eachof which groups is linked to the N atom via a sp³ carbon, each of whichis optionally substituted by C₃₋₈ cycloalkyl, aryl (optionallysubstituted by one or more methyl, ethyl, halogen, CH₂CN, CF₃, NHSO₂CH₃,OH, ═O, methoxy, OCF₃), optionally benzo-fused heteroaryl (optionallysubstituted by one or more methyl, halogen, CH₂CN, CF₃, NHSO₂CH₃,methoxy, OH, ═O, OCF₃), OH, aryloxy (optionally substituted by one ormore methyl, halogen, CH₂CN, OH, ═O, CF₃, NHSO₂CH₃, methoxy, OCF₃), CN,CF₃, C₁₋₆ alkoxy, C₃₋₈ cycloalkyloxy, CONH(C₃₋₈ cycloalkyl), adamantyl,or (optionally benzo-fused) heteroaryloxy (optionally substituted by oneor more methyl, halogen, CH₂CN, CF₃, NHSO₂CH₃, OH, ═O, methoxy, OCF₃).

[0089] More preferably R⁴ is n-hexyl, 3-phenylpropyl, 3-phenyloxypropyl,3-cyclohexylpropyl, 5-methylhexyl, 2-phenyloxyethyl,(4-cyanomethyl)benzyl, 2-cyclohexyloxyethyl, 2-benzyloxyethyl,3-cyclohexylprop-2-en-1-yl, 2-(cyclohexylcarbonyl)ethyl,3-(2-methylphenyl)propyl, 3-phenylprop-2-en-1-yl, 2-(indol-3-yl)ethyl,3-cyclohexyl-3-hydroxypropyl, (indan-2-yl)methyl,3-(4-fluorophenyl)propyl, 3-(thien-2-yl)propyl, 3-(thien-3-yl)propyl,3-(pyrid-2-yl)propyl, 3-(3-methylthien-2-yl)propyl,3-(thien-2-yl)prop-2-en-1-yl, 3-(thien-3-yl)prop-2-e-1yl,3-(pyrid-2-yl)prop-2-en-1-yl, 3-(3-methylthien-2-yl)prop-2-en-1-yl,3-(3-methylpyrid-2-yl)prop-2-en-1-yl or 3-(2-methoxyphenyl)propyl.

[0090] Yet more preferably R⁴ is n-hexyl, 3-phenylpropyl,(4-cyanomethyl)benzyl, 2-benzyloxyethyl, 3-cyclohexylprop-2-en-1-yl,2-(indol-3-yl)ethyl, 3-(2-methylphenyl)propyl, 3-(4-fluorophenyl)propyl,3-(pyrid-2-yl)propyl, 3-phenylprop-2-en-1-yl,3-cyclohexyl-3-hydroxypropyl, 3-(thien-2-yl)propyl,3-(thien-3-yl)propyl, 3-(3-methylthien-2-yl)propyl,3-(thien-2-yl)prop-2-en-1-yl, 3-(thien-3-yl)prop-2-en-1-yl,3-(pyrid-2-yl)prop-2-en-1-yl, 3-(3-methylthien-2-yl)prop-2-en-1-yl,3-(6-methylpyrid-2-yl)prop-2-en-1-yl or 3-(2-methoxyphenyl)propyl.

[0091] Preferably R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are each taken separatelyand are H.

[0092] A preferred group of substances are those in which the “Ar” ring,R¹, R², R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰, q and (X)_(n)have thevalues as detailed in Example below.

[0093] A most preferred group of substances are those mentioned inExamples, especially Examples 1, 5, 6, 10-13, 18, 20, 25-28, 32-34, 36,38, 40, 42, 45, 47, 48, 57, 62, 67-69, 76, 79, 80, 84, 88, 90, 92, 97,99, 102, 113, 114, 118, 119, 122-124, 136, 139 and 143, and the saltsand prodrugs thereof, even more especially those of Examples 1, 5, 10,12, 13, 26, 28, 36, 40, 45, 47, 48, 62, 68, 69, 79, 80, 84, 88, 90, 97,99, 102, 113, 118, 114, 119, 122-124, 136, 139 and 143 and the salts andprodrugs thereof. Yet more preferred are the compounds of Examples 1,10, 13, 26, 28, 62, 68, 69, 79, 80, 84, 88, 90, 97, 102, 113, 114, 118,119, 12, 123, 124, 136, 139, and 143 and the salts and prodrugs thereof.Most preferred are the compounds of Examples 1, 10, 26, 79, 97, 102,118, 139 and 143 and the salts and prodrugs thereof.

[0094] The invention further provides synthetic methods for theproduction of compounds and salts of the invention, which are describedbelow and in the Examples and Preparations. The skilled man willappreciate that the compounds of the invention could be made by methodsother than those herein described, by adaptation of the methods hereindescribed and/or adaptation of methods known in the art, for example theart described herein, or using standard textbooks such as

[0095] “Comprehensive Organic Transformations—A Guide to FunctionalGroup Transformations”, R C Larock, VCH (1989 or later editions),

[0096] “Advanced Organic Chemistry—Reactions, Mechanisms and Structure”,J. March, Wiley-Interscience (3rd or later editions),

[0097] “Organic Synthesis—The Disconnection Approac”, S Warren (Wiley),(1982 or later editions),

[0098] “Designing Organic Syntheses” S Warren (Wiley) (1983 or latereditions),

[0099] “Guidebook To Organic Synthesis” R K Mackie and D M Smith(Longman) (1982 or later editions), etc.,

[0100] and the references therein as a guide.

[0101] It is to be understood that the synthetic transformation methodsmentioned herein are exemplary only and they may be carried out invarious different sequences in order that the desired compounds can beefficiently assembled. The skilled chemist will exercise his judgementand skill as to the most efficient sequence of reactions for synthesisof a given target compound. For example, substituents may be added toand/or chemical transformations performed upon, different intermediatesto those mentioned hereinafter in conjunction with a particularreaction. This will depend inter alia on factors such as the nature ofother functional groups present in a particular substrate, theavailability of key intermediates and the protecting group strategy (ifany) to be adopted. Clearly, the type of chemistry involved willinfluence the choice of reagent that is used in the said syntheticsteps, the need, and type, of protecting groups that are employed, andthe sequence for accomplishing the synthesis. The procedures may beadapted as appropriate to the reactants, reagents and other reactionparameters in a manner that will be evident to the skilled person byreference to standard textbooks and to the examples providedhereinafter.

[0102] It will be apparent to those skilled in the art that sensitivefunctional groups may need to be protected and deprotected duringsynthesis of a compound of the invention. This may be achieved byconventional methods, for example as described in “Protective Groups inOrganic Synthesis” by T W Greene and P G M Wuts, John Wiley & Sons Inc(1999), and refernces therein. Functional groups which may desirable toprotect include oxo, hydroxy, amino and carboxylic acid. Suitableprotecting groups for oxo include acetals, ketals (e.g. ethylene ketals)and dithianes. Suitable protecting groups for hydroxy includetrialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl,tert-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl.Suitable protecting groups for amino include tert-butyloxycarbonyl,9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protectinggroups for carboxylic acid include C₁₋₆ alkyl or benzyl esters.

[0103] In the Methods below, unless otherwise specified, thesubstituents are as defined above with reference to the compounds offormula (I).

[0104] The invention provides a process for the preparation of compoundsof formula I as defined above, or a pharmacutically or veterinarilyacceptable derivative thereof, which comprises:

[0105] (a) for compounds of formula I in which q is 0 and R¹ representsNY²WY¹, reacting a compound of formula II,

[0106]  with a compound of formula III,

Z¹—WY¹  III

[0107] wherein Z¹ is a suitable leaving group, such as halogen orY¹SO₂O—;

[0108] (b) for compounds of formula I in which q is 0 and R⁶ and R⁷ bothrepresent H, reduction of a compound of formula IV,

[0109]  using a suitable reducing agent;

[0110] (c) for compounds of formula I in which q is 0 and R⁹ and R¹⁰both represent H, reduction of a compound of formula V,

[0111]  using a suitable reducing agent;

[0112] (d) for compounds of formula I in which q is 0 and R¹ and R² areattached to adjacent carbon atoms and are taken together with the carbonatoms to which they are attached to represent Het^(1a), in whichHet^(1a) represents an imidazolo unit, reaction of a correspondingcompound of formula VI,

[0113]  with a compound of formula VII,

R^(y)CO₂H  VII

[0114] wherein R^(y) represents H or any of the optional substituents onHet^(1a) (as defined above), preferably H, C₁₋₄ alkyl or C₁₋₄ haloalkyl;

[0115] (e) where q is 0, reacting a compound of formula VIII,

[0116]  with a compound of formula IX,

R⁴—Lg  IX

[0117] wherein Lg is a leaving group;

[0118] (f) for compounds of formula I in which q is 0 and R⁶, R⁷, R⁹ andR¹⁰ are all H, reduction of a compound of formula X,

[0119]  with a suitable reducing agent;

[0120] (g) for compounds of formula I in which q is 0 and R¹ representsOH, reacting a compound of formula II in which Y² is H, as definedabove, with fluoroboric acid and isoamyl nitrite;

[0121] (h) for compounds of formula I in which q is 0 and R¹ representsCl, reacting a compound of formula II in which Y² is H, as definedabove, with sodium nitrite in the presence of dilute acid, followed byreaction with copper (I) chloride in the presence of concentrated acid;

[0122] (i) for compounds of formula I in which q is 1, reacting acompound of formula I where q is 0 with a suitable oxidising agent suchas aqueous hydrogen peroxide; or

[0123] (j) for compounds of formula I where q is 0, by reduction of acorresponding compound of formula XXXI,

[0124] where R^(4a)CH₂ takes the same meaning as R⁴ as defined above,

[0125] and where desired or necessary converting the resulting compoundof formula I into a pharmaceutically or veterinarily acceptablederivative or vice versa.

[0126] In process (a), the reaction may be carried out at between 0° C.and room temperature in the presence of a suitable base (e.g. pyridine)and an appropriate organic solvent (e.g. dichloromethane).

[0127] Compounds of formula II may be prepared by reduction of acorresponding compound of formula XI or formula XII,

[0128] in the presence of a suitable reducing agent, such as lithiumaluminium hydride. The reaction may be carried out at between roomtemperature and reflux temperature in the presence of a suitable solvent(e.g. tetrahydrofuran).

[0129] Compounds of formula XI and XII may be prepared by reduction ofthe corresponding —NO₂ compounds under conditions that are well known tothose skilled in the art (e.g. using H₂/Raney Ni or in the presence ofCaCl₂ and iron powder, in the presence of a suitable solvent system(e.g. EtOH, EtOAc and/or water)). The skilled person will appreciatethat, in preparing a compound of formula II, in which Y² is H, from sucha corresponding —NO₂ compound, the two above-mentioned reduction stepsmay be performed in the same step or sequentially in any order.

[0130] The said corresponding —NO₂ compounds may be prepared by reactionof a compound of formula XII or formula XIV, as appropriate,

[0131] wherein L¹ represents a suitable leaving group [such as halo(e.g. chloro or bromo)], L² represents a suitable leaving group (such asC₁₋₃ alkoxy) and R³ is as defined above, with a compound of formula XV,

R⁴NH₂  XV

[0132] The reaction may be carried out at between room temperature andreflux temperature in the presence of a suitable base (e.g. NaHCO₃) andan appropriate organic solvent (e.g. dimethylformamide), or at a highertemperature (e.g. between 50 and 200° C., preferably between 100 and160° C.) in the presence of neat compound of formula XV.

[0133] Compounds of formula XIII and XIV may be prepared in accordancewith standard techniques. For example, compounds of formula XIII and XIVmay be prepared by reacting a corresponding compound of formula XVI orXVII,

[0134] with a compound of formula XVIII or XIX respectively,

N₂CHR⁵COL²  XVIII

N₂CHR⁸COL²  XIX

[0135] wherein L² is as defined above. The reaction may be carried outat room temperature in the presence of a suitable catalyst [e.g.Rh₂(OAc)₄] and an appropriate non-protic organic solvent (e.g.dichloromethane).

[0136] Compounds of formula XVI and formula XVII are available or can beprepared using known techniques. Compounds of formula XVI and formulaXVII may, for example, be prepared from corresponding compounds offormula XX,

[0137] for example by performing a Wittig reaction using an appropriateprovider of the nucleophilic group RO₂C—CR⁵H⁻ or RO₂C—CR⁸H⁻ (wherein Rrepresents lower (e.g. C₁₋₃) alkyl), as appropriate, under conditionsthat are well known to those skilled in the art. The —CO₂R group of theresulting compound may be converted to an appropriate —CII₂L¹ groupusing standard techniques (e.g. reduction of the ester to the primaryalcohol and conversion of the latter to an alkyl halide) underconditions that are well known to those skilled in the art.

[0138] In processes (b) and (c), suitable reducing agents includelithium aluminium hydride. The reaction may be carried out at betweenroom temperature and reflux temperature in the presence of a suitablesolvent (e.g. tetrahydrofuran).

[0139] Compounds of formula II may be prepared by reduction of thecorresponding compound of formula XXX,

[0140] by analogy to the process steps mentioned above.

[0141] Compounds of formula IV and V may be prepared respectively fromcompounds of formula XXI and XXII,

[0142] wherein L³ represents a group that is capable of undergoingfunctional group transformations (e.g. cyano) using standard functionalgroup substitution or conversion techniques.

[0143] For example:

[0144] (1) Compounds of formula IV and V in which R¹ represents1,2,4-triazol-3-yl may be prepared by reaction of an appropriatecompound of formula XXI or XXII in which L³ represents —CN with HCl(gas) in the presence of an appropriate lower alkyl alcohol (e.g.ethanol), for example at between 0° C. and room temperature, followed byreaction of the resultant intermediate with formic acid hydrazide (e.g.at reflux temperature, with or without the presence of a suitableorganic solvent (e.g. methanol), followed by, if necessary, removing thesolvent and heating the resultant residue to a high temperature (e.g.about 150° C.)).

[0145] (2) Compounds of formula IV and V in which R¹ representsimidazol-2-yl may be prepared by reaction of an appropriate compound offormula XX or XXII in which L³ represents —CN with HCl (gas) in thepresence of an appropriate lower alkyl alcohol (e.g. ethanol), forexample at between 0° C. and room temperature, followed by reaction ofthe resultant intermediate with aminoacetaldehyde dialkylacetal (e.g.dimethylacetal) (e.g. at or around reflux temperature in the presence ofan appropriate solvent, such as methanol).

[0146] (3) Compounds of formula IV and V in which R¹ represents1,2,3-triazol-5-yl may be prepared by reaction of an appropriatecompound of formula XX or XXI in which L³ represents —CN withdiazomethane, or a protected (e.g. trialkylsilyl) derivative thereof,for example at between 0° C. and room temperature in the presence of asuitable base (e.g. n-BuLi) and, optionally, an appropriate organicsolvent (e.g. THF), followed by removal of the protecting group asnecessary.

[0147] (4) Compounds of formula IV and V in which R¹ representsbenzimidazol-2-yl may be prepared by reaction of an appropriate compoundof formula XX or XXII in which L³ represents C═NH(OEt) with1,2-diaminobenzene. The reaction may be carried out in a solvent such asmethanol, at an elevated temperature (such as the reflux temperature ofthe solvent). Preparations 81, etc. provide further details.

[0148] Compounds of formula IV and V in which R¹ represents Het¹ mayalso be prepared from compounds of formula XI and XII respectivelyaccording to the following scheme:

[0149] wherein Het¹ is defined above. Further details may be found inPreparations 67, 68, etc. below.

[0150] Compounds of formula XXI and XXII may be prepared in analogousfashion to methods described herein, for example those describedhereinbefore for preparation of compounds of formula II.

[0151] Other compounds of formula (IV) and (V) may be prepared byanalogy with methods described herein (e.g. by analogy with methodsdescribed hereinbefore for preparation of compounds of formula XI andXII (and especially the corresponding —NO₂ compound)).

[0152] In process (d), the reaction may be carried out by heating underreflux, with or without the presence of an appropriate organic solvent.

[0153] Compounds of formula VI may be prepared using known techniques.For example, compounds of formula VI may be prepared by nitration (atthe 4-position) of a corresponding 3-aminobenzene compound (a compoundof formula II), which latter compound may be activated by converting the3-amino group to a 3-amido group, followed by hydrolysis of the amideand reduction of the 4-nitrobenzene compound. All of these reactions maybe performed using techniques that are familiar to the skilled person,and are illustrated in Preparations 45-48, etc. below.

[0154] In process (e), suitable leaving groups that Lg may representinclude halogen, such as bromine, or a sulphonate group such astosylate. The reaction may be carried out in a solvent that does notadversely affect the reaction (for example dimethylformamide), at anelevated temperature (for example 50° C.), in the presence of a base(for example sodium hydrogen carbonate). A catalyst such as sodiumiodide may optionally be added.

[0155] Compounds of formula VIII may be prepared from compounds offormula XXV,

[0156] wherein Pg represents a suitable protecting group. Suitableprotecting groups include allyl, which may be removed using a palladium(0) catalyst and N,N-dimethylbarbituric acid (see Preparation 53, etc.below). Compounds of formula XXV may be prepared using analogous methodsto those described herein for the preparation of compounds of formula I.

[0157] In process (f), suitable reducing agents include lithiumaluminium hydride. The reaction may be carried out in a solvent thatdoes not adversely affect the reaction (for example tetrahydrofuran), atan elevated temperature (for example the reflux temperature of thesolvent).

[0158] Compounds of formula X may be prepared by reacting a compound offormula XXVI with a compound of formula XXVII in the presence of anoxidizing agent. Suitable oxidizing agents include manganese dioxide.The reaction may be carried out in a solvent that does not adverselyaffect the reaction (for example dioxan), at an elevated temperaturesuch as the reflux temperature of the solvent (for example seePreparation 77, etc. below). The intermediate compounds XXIXa areisolatable using suitable conditions (e.g. see Preparation 58).

[0159] Compounds of formula XXVI may be prepared from compounds offormula XXVIII, by reaction of the corresponding ketone with hydrazinemonohydrate using known techniques (and as described in Preparation 76,etc. below).

[0160] Process (f) is particularly useful when Ar represents anoptionally benzo-fused 5- or 6-membered heteroaryl ring. A similarmethodology may be used to obtain compounds of formula II: the precursornitro compound may be prepared from a compound of formula XX, as definedabove, using the steps described above (see for example Preparations57-61, etc.).

[0161] In process (g), the reaction may be carried out in a solvent thatdoes not adversely affect the reaction (for example ethanol), firstbelow room temperature and then at an elevated temperature (Examples 79,etc. provide further details).

[0162] In process (h), suitable acids include dilute aqueoushydrochloric acid and concentrated hydrochloric acid, respectively. Thereaction may be carried out at or around room temperature, finishing atan elevated temperature (for example 90° C.). Examples 51 providefurther details.

[0163] In process (j), the compound of formula XXXI may be prepared byacylation of the compound of formula VIH as defined above, with anacylating agent of the formula R^(4a)CO—L_(g), where L_(g) is a suitableleaving group as defined above with respect to (e), and includeshalogen, (alkyl, haloalkyl or aryl)sulphonate, OCOR^(4a) (i.e. an acidanhydride) and the like, well known to those practising in the art. Seefor example the conditions used for Preparation 47.

[0164] It will be apparent to those skilled in the art that compounds offormula I may be converted to other compounds of formula I using knowntechniques. For example, compounds of formula I in which Y¹ representsalkoxycarbonyl may be converted to compounds in which Y¹ representsalkyl substituted by OH, by reduction using LiAlH₄ (Example 57 providesfurther details). Similarly, intermediate compounds may beinterconverted using known techniques (see for example Preparation 85).

[0165] The intermediate compounds such as those of formulae III, XV,XVIII, XIX, XX, VII, IX, XXVI, XXVII and XXVIII, and derivativesthereof, when not commercially available or not subsequently described,may be obtained either by analogy with the processes described herein,or by conventional synthetic procedures, in accordance with standardtechniques, from readily available starting materials using appropriatereagents and reaction conditions.

[0166] The invention further provides the intermediate compounds offormulae II, IV, V, VI, VIII, X, X^(a), XI, XII, XIII, XIV, XXI, XXII,XXIII, XXIV, XXV, XXIX, XXIX^(a), XXX, XXXI as defined above.

[0167] Where desired or necessary, the compound of formula (I) can beconverted into a pharmaceutically acceptable salt thereof, convenientlyby mixing together solutions of a compound of formula (I) and thedesired acid or base, as appropriate. The salt may be precipitated fromsolution and collected by filtration, or may be collected by other meanssuch as by evaporation of the solvent. Both types of salt may also beformed or interconverted using ion-exchange resin techniques.

[0168] The compounds of the invention may be purified by conventionalmethods, for example separation of diastereomers may be achieved byconventional techniques, e.g. by fractional crystallisation,chromatography or H.P.L.C. of a stereoisomeric mixture of a compound offormula (I) or a salt thereof An individual enantiomer of a compound offormula (I) may also be prepared from a corresponding optically pureintermediate or by resolution, such as by H.P.L.C. of the correspondingracemate using a suitable chiral support or by fractionalcrystallisation of the diastereomeric salts formed by reaction of thecorresponding racemate with a suitably optically active base or acid.

[0169] The compounds of the invention are useful because they possesspharmacological activity in animals, especially mammals includinghumans. They are therefore indicated as pharmaceuticals and, inparticular, for use as animal medicaments.

[0170] According to a further aspect of the invention there is providedthe compounds of the invention for use as medicaments, such aspharmaceuticals and animal medicaments. By the term “treatment”, weinclude both therapeutic (curative) or prophylactic treatment.

[0171] In particular, the substances of the invention have been found tobe useful in the treatment of diseases and conditions modulated viaopiate receptors, such as irritable bowel syndrome; constipation;nausea; vomiting; pruritus; eating disorders; opiate overdoses;depression; smoking and alcohol addiction; sexual dysfunction; shock;stroke; spinal damage and/or head trauma; and conditions characterisedby having pruritis as a symptom.

[0172] Thus, according to a further aspect of the invention there isprovided the use of the compounds of the invention in the manufacture ofa medicament for the treatment of a disease modulated via an opiatereceptor. There is further provided the use of the compounds of theinvention in the manufacture of a medicament for the treatment of asirritable bowel syndrome; constipation; nausea; vomiting; pruritus;eating disorders; opiate overdoses; depression; smoking and alcoholaddiction; sexual dysfunction; shock; stroke; spinal damage and/or headtrauma; and conditions characterised by having pruritis as a symptom.

[0173] The compounds of the invention are thus expected to be useful forthe curative or prophylactic treatment of pruritic dermatoses includingallergic dermatitis and atopy in animals and humans. Other diseases andconditions which may be mentioned include contact dermatitis, psoriasis,eczema and insect bites.

[0174] Thus, the invention provides a method of treating or preventing adisease modulated via an opiate receptor. There is further provided amethod of treating irritable bowel syndrome; constipation; nausea;vomiting; pruritus; eating disorders; opiate overdoses; depression;smoking and alcohol addiction; sexual dysfunction; shock; stroke; spinaldamage and/or head trauma; or a medical condition characterised bypruritus as a symptom in an animal (e.g. a mammal), which comprisesadministering a therapeutically effective amount of a compound of theinvention to an animal in need of such treatment.

[0175] The compounds of the invention will normally be administeredorally or by any parenteral route, in the form of pharmaceuticalpreparations comprising the active ingredient, optionally in the form ofa non-toxic organic, or inorganic, acid, or base, addition salt, in apharmaceutically acceptable dosage form. Depending upon the disorder andpatient to be treated, as well as the route of administration, thecompositions may be administered at varying doses (see below).

[0176] While it is possible to administer a compound of the inventiondirectly without any formulation, the compounds are preferably employedin the form of a pharmaceutical, or veterinary, formulation comprising apharmaceutically, or veterinarily, acceptable carrier, diluent orexcipient and a compound of the invention. The carrier, diluent orexcipient may be selected with due regard to the intended route ofadministration and standard pharmaceutical, and/or veterinary, practice.Pharmaceutical compositions comprising the compounds of the inventionmay contain from 0.1 percent by weight to 90.0 percent by weight of theactive ingredient.

[0177] The methods by which the compounds may be administered forveterinary use include oral administration by capsule, bolus, tablet ordrench, topical administration as an ointment, a pour-on, spot-on, dip,spray, mousse, shampoo, collar or powder formulation or, alternatively,they can be administered by injection (eg subcutaneously,intramuscularly or intravenously), or as an implant. Such formulationsmay be prepared in a conventional manner in accordance with standardveterinary practice.

[0178] The formulations will vary with regard to the weight of activecompound contained therein, depending on the species of animal to betreated, the severity and type of infection and the body weight of theanimal. For parenteral, topical and oral administration, typical doseranges of the active ingredient are 0.01 to 100 mg per kg of body weightof the animal. Preferably the range is 0.1 to 10 mg per kg.

[0179] In any event, the veterinary practitioner, or the skilled person,will be able to determine the actual dosage which will be most suitablefor an individual patient, which may vary with the species, age, weightand response of the particular patient. The above dosages are exemplaryof the average case; there can, of course, be individual instances wherehigher or lower dosage ranges are merited, and such are within the scopeof this invention.

[0180] For veterinary use, the compounds of the invention are ofparticular value for treating pruritus in domestic animals such as catsand dogs and in horses.

[0181] As an alternative for treating animals, the compounds may beadministered with the animal feedstuff and for this purpose aconcentrated feed additive or premix may be prepared for mixing with thenormal animal feed.

[0182] For human use, the compounds are administered as a pharmaceuticalformulation containing the active ingredient together with apharmaceutically acceptable diluent or carrier. Such compositionsinclude conventional tablet, capsule and ointment preparations which areformulated in accordance with standard pharmaceutical practice.

[0183] Compounds of the invention may be administered either alone or incombination with one or more agents used in the treatment or prophylaxisof disease or in the reduction or suppression of symptoms. Examples ofsuch agents (which are provided by way of illustration and should not beconstrued as limiting) include antiparasitics, eg fipronil, lufenuron,imidacloprid, avermectins (eg abamectin, ivermectin, doraamectin),milbemycins, organophosphates, pyrethroids; antihistamines, egchlorpheniramine, trimeprazine, diphenhydramine, doxylamine;antifungals, eg fluconazole, ketoconazole, itraconazole, griseofulvin,amphotericin B; antibacterials, eg enroflaxacin, marbofloxacin,ampicillin, amoxycillin; anti-inflammatonies eg prednisolone,betamethasone, dexamethasone, carprofen, ketoprofen; dietarysupplements, eg gamma-linoleic acid; and emollients. Therefore, theinvention further provides a product containing a compound of theinvention and one or more selected compounds from the above list as acombined preparation for simultaneous, separate or sequential use in thetreatment of diseases modulated via opiate receptors

[0184] The skilled person will also appreciate that compounds of theinvention may be taken as a single dose or on an “as required” basis(i.e. as needed or desired).

[0185] Thus, according to a further aspect of the invention there isprovided a pharmaceutical, or veterinary, formulation including acompound of the invention in admixture with a pharmaceutically, orveterinarily, acceptable adjuvant, diluent or carrier.

[0186] Compounds of the invention may also have the advantage that, inthe treatment of human and/or animal patients, they may be moreefficacious than, be less toxic than, have a broader range of activitythan, be more potent than, produce fewer side effects than, be moreeasily absorbed than, or they may have other useful pharmacologicalproperties over, compounds known in the prior art.

[0187] The biological activities of the compounds of the presentinvention were determined by the following test method.

[0188] Biological Test

[0189] Compounds of the present invention have been found to displayactivity in three opioid receptor binding assays selective for the mu,kappa and delta opioid receptors in dog brain. The assays were conductedby the following procedure.

[0190] Laboratory bred beagles were used as a source of dog braintissue. Animals were euthanaised, their brains removed and thecerebellum discarded. The remaining brain tissue was sectioned intosmall pieces approximately 3 g in weight and homogenised in 50 mM TrispH 7.4 buffer at 4° C. using a Kinematica Polytron tissue homogeniser.The resulting homogenate was centrifuged at 48,400×g for 10 minutes andthe supernatant discarded. The pellet was resuspended in Tris buffer andincubated at 37° C. for 10 minutes. Centrifugation, resuspension andincubation steps were repeated twice more, and the final pellet wasresuspended in Tris buffer and stored at −80° C. Membrane materialprepared in this manner could be stored for up to four weeks prior touse.

[0191] For mu, kappa and delta assays, increasing concentrations ofexperimental compound (5×10⁻¹² to 10⁻⁵M), Tris buffer and ³H ligand,(mu=[D-Ala²,N-Me-Phe⁴,Gly-ol⁵]-Enkephalin, DAMGO; kappa=U-69,593;delta=Enkephalin, [D-pen^(2,5)] DPDPE), were combined in polystyrenetubes. The reaction was initiated by the addition of tissue, and themixture was incubated at room temperature for 90 minutes. The reactionwas terminated by rapid filtration using a Brandel Cell Harvester™through Betaplate™ GF/A glass fibre filters pre-soaked in 50 mM Tris pH7.4, 0.1% polyethylenimine buffer. The filters were then washed threetimes with 0.5 ml ice-cold Tris pH 7.4 buffer. For mu and delta assays,washed filters were placed in bags and Starscint™ scintillant added, forthe kappa assay Meltilex™ B/HS solid scintillant was used. Bagscontaining the filters and scintillant were heat sealed and counted by aBetaplate™ 1204 beta counter.

[0192] Duplicate samples were run for each experimental compound and thedata generated was analysed using IC₅₀ analysis software in GraphpadPrism. Ki values were calculated using Graphpad Prism according to thefollowing formula:

Ki=IC ₅₀/1+[³H ligand]/K _(D)

[0193] where IC₅₀ is the concentration at which 50% of the ³H ligand isdisplaced by the test compound and K_(D) is the dissociation constantfor the ³H ligand at the receptor site.

[0194] Biological Activity

[0195] The Ki values of certain compounds of the present invention inthe opioid receptor binding assays were determined, and the compounds ofExamples 1, 6, 8, 14-16, 19 and 21-24 were found to have Ki values of4000 nM or less for the μ receptor.

[0196] It is believed that the methods used in the following Examplesproduce compounds having the relative stereochemistry shown below, andsuch compounds are preferred:

[0197] wherein R¹⁻⁴ and (X)_(n) are as defined above.

[0198] The invention is illustrated by the following Examples andPreparations in which the following abbreviations may be used:

[0199] APCI=atmospheric pressure chemical ionization

[0200] DMF=dimethylformamide

[0201] DMSO=dimethylsulphoxide

[0202] d (in relation to time)=day

[0203] d (in relation to NMR)=doublet

[0204] ES (in relation to MS)=electrospray

[0205] EtOAc=ethyl acetate

[0206] EtOH=ethanol

[0207] h=hour

[0208] MeOH=methanol

[0209] min=minute

[0210] MS=mass spectrum

[0211] n-BuOH=n-butanol

[0212] ODS=octadecylsilyl

[0213] TBF=tetrahydrofuran

[0214] TSP=thermospray

[0215] Melting points were determined using a Gallenkamp melting pointapparatus and are uncorrected. Nuclear magnetic resonance (NMR) spectraldata relate to ¹H and were obtained using a Varian Unity 300 or 400spectrometer, the observed chemical shifts (δ) being consistent with theproposed structures. Mass spectral (MS) data were obtained on a FisonsInstruments Trio 1000, or a Fisons Instruments Trio 1000 APCI, or aFinnigan Navigator MS, or a Micromass Platform LC spectrometer. Thecalculated and observed ions quoted refer to the isotopic composition oflowest mass. Room temperature means 20 to 25° C. The mass spectrometerwhich is used as a detector on the analytical HPLC-MS system is aMicromass VG Platform II, running on Masslynx/Openlynx software. Thesystem can run positive and negative ion with either Electrospray orAPCI probes and is calibrated to 1972 Daltons, it collects full Diodearray data from 190 nm to 600 nm.

[0216] HPLC means high performance liquid chromatography. HPLCconditions used were:

[0217] Condition 1: Rainin Dynamax™ column, 8μ ODS, 24×300 mm, columntemperature 40° C., flow rate 45 ml/min, eluting with methanol:water(70:30), UV detection of product at 246 nm.

[0218] Condition 2: Rainin Dynamax™ column, 5μ ODS, 21.6×250 mm, columntemperature 40° C., flow rate 5 ml/min, eluting with acetonitrile:water(50:50), UV detection of product at 246 nm.

[0219] Condition 3: Rainin Dynamax™ column, 8μ ODS, 41×250 mm, columntemperature 40° C., flow rate 45 ml/min, eluting with acetonitrile:0.1Maqueous ammonium acetate buffer (50:50), UV detection of product at 235nm.

[0220] Condition 4: Phenomenex Magellan™ column, 5μC₁₈ silica, 21.2×150mm, column temperature 40° C., flow rate 20 ml/min, eluting with agradient of acetonitrile:0.1M aqueous ammonium acetate buffer (30:70 to95:5 over 10 min), UV detection of product at 220 nm.

[0221] Condition 5: Phenomenex Magellan™ column, 5μ ODS, 21.2×150 mm,column temperature 40° C., flow rate 20 ml/min, eluting with a gradientof acetonitrile:0.1M aqueous ammonium acetate buffer (5:95 to 95:5 over20 min), UV detection of product at 215 nm.

[0222] Condition 6: Phenomenex Magellan™ column, 5μ C₁₈ silica, 4.6×150mm, column temperature 40° C., flow rate 1 ml/min, eluting with agradient of acetonitrile:0.1M aqueous heptanesulphonic acid (10:90 to90:10 over 30 min), UV detection of product at 220 nm.

[0223] Condition 7: Phenomenex Magellan™ column, 5μ C₁₈ silica, 21.2×150mm, column temperature 40° C., flow rate 20 ml/min, eluting with agradient of acetonitrile:0.05M aqueous ammonium acetate buffer (50:50for 15 min then 50:50 to 90:10over 5 min), UV detection of product at220 nm.

[0224] Condition 8: Phenomenex Magellen™ column, 5μ C₁₈ silica, 21.2×150mm, column temperature 40° C., flow rate 20 ml/min, eluting with agradient of acetonitrile:0.1M aqueous ammonium acetate buffer (15:85 to85:15), UV detection of product at 220 nm.

[0225] Condition 9: Phenomenex Magellen™ column, 5μ ODS, 10×150 mm,column temperature 40° C., flow rate 5 ml/min, eluting with a gradientof acetonitrile:0.1M aqueous ammonium acetate buffer (5:95 to 30:70 over5 min then 30:70 for a further 20 min), UV detection of product at 225nm.

[0226] Condition 10: Phenomenex Magellan™ column, 5μC₁₈ silica,21.2×150mm, column temperature 40° C., flow rate 20 ml/min, eluting witha gradient of acetonitrile:0.1M aqueous ammonium acetate (5:95 to 40:60over 5 min then 40:60 for a further 25 min), UV detection of product at210 nm.

[0227] Condition 11: Phenomenex Magellan™ column, 5μ ODS, 10×150 mm,column temperature 40° C., flow rate 5 ml/min, eluting with a gradientof acetonitrile:water (5:95 to 55:45 over 5 min), UV detection ofproduct at 210 nm.

[0228] The free base form of the azabicycles could be obtained from thehydrochloride or acetate salts, for example, in the following way. Thesalt (0.3 mmol) was dissolved in dichloromethane (20 ml) and washed withsaturated aqueous sodium hydrogen carbonate solution (20 ml). The basicmixture was separated and the aqueous layer was extracted withdichloromethane (2×20 ml). The combined organic extracts were dried(Na₂SO₄) and concentrated in vacuo to give the free base.

[0229] SPE cartridge refers to a solid phase extraction cartridge. Thesecan be commercially obtained from Varian (Mega Bond Elut®) or Isolute™.

EXAMPLE 1

[0230]

[0231] To a solution of3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine(Preparation 8, 28 mg, 0.09 mmol) in dichloromethane (2 ml), at 0° C.under nitrogen was added pyridine (20 μl, 0.24 mmol) and thenmethanesulfonylchloride (25 μl, 37 mg, 0.32 mmol) over 5 minutes. Themixture was allowed to warm to room temperature and was then stirred for2 hours. The mixture was concentrated in vacuo and the residue waspurified by silica (5 g) column chromatography eluting with 80:20:1ethyl acetate:hexane:ammonia solution (0.880). Product-containingfractions were combined and concentrated in vacuo to give the titlecompound as a colourless oil (18 mg, 52%).

[0232] NMR (CDCl₃) δ: 1.56 (s, 3H), 1.77 (m, 4H), 2.48 (t, 2H), 2.66 (t,2H), 2.80 (d, 2H), 3.01 (s, 3H), 3.05 (d, 2H), 7.01 (d, 1H), 7.07 (m,2H), 7.14-7.3 (m, 6H).

[0233] MS (thermospray): M/Z [MH⁺] 385.4; C₂₂H₂₈N₂SO₂+H requires 385.2

EXAMPLE 2N-{3-[6-Methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamideAcetate Salt

[0234]N-{3-[6-Methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide(Example 1, 260 mg; 0.67 mmol) was purified further by preparative HPLC(condition 3). Combination and evaporation of pure fractions gave thetitle compound as a white solid (87 mg)

[0235] mp 116-117° C.

[0236] NMR (CD₃OD) δ: 1.45 (s, 3H), 1.93 (m, 5H), 2.09 (s, 2H), 2.67 (t,2H), 2.86 (t, 2H), 2.93 (s, 3H), 3.05 (d, 2H) 3.46 (d, 2H), 7.04 (m,2H), 7.10-7.33 (m, 7H)

EXAMPLE 3

[0237]

[0238] To a solution of3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine(Preparation 8, 110 mg, 0.36 mmol) in dichloromethane (4 ml), at 0° C.under nitrogen was added pyridine (56 μl, 0.72 mmol) then dropwise over5 minutes ethanesulfonylchloride (67 μl, 92 mg, 0.72 mmol). The mixturewas allowed to warm to room temperature and was stirred for 16 hours.Further pyridine (56 μl, 0.72 mmol) and ethanesulfonylchloride (67 μl,92 mg, 0.72 mmol) were added and the mixture was stirred for 2 hours.The crude mixture was purified by silica (40 g) column chromatographyeluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880).Product-containing fractions were combined and concentrated in vacuo togive the title compound as a colourless oil (48 mg, 34%).

[0239] NMR (CDCl₃) δ: 1.39 (t, 3H), 1.57 (s, 3H), 1.76 (m, 4H), 2.48 (t,2H), 2.66 (t, 2H), 2.80 (d, 2H),3.04 (d,2H),3.12 (q,3H), 6.97-7.11 (m,3H), 7.11-7.33 (m, 6H).

[0240] MS (thermospray): M/Z [MH³⁰ ] 399.2; C₂₃H₃₀N₂SO₂+H requires 399.2

EXAMPLE 4

[0241]

[0242] To a solution of3-[3-(3-cyclohexylpropyl)-6-methyl-3-azabicyclo[3.1.0]-hex-6-yl]phenylamine(Preparation 10, 25 mg, 0.08 mmol) in dichloromethane (2 ml) at 0° C.under nitrogen was added pyridine (20 ∥l, 0.24 mmol) then dropwise over5 minutes methanesulfonylchloride (25 μl, 37 mg, 0.32 mmol). The mixturewas allowed to warm to room temperature and was stirred for 90 minutes.Further methanesulfonylchloride (10 μl, 15 mg, 0.13 mmol) was added andthe mixture was stirred for 1 hour. The mixture was concentrated invacuo and the residue was purified by silica (5 g) column chromatographyeluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880).Product-containing fractions were combined and concentrated in vacuo togive the title compound as a pale yellow oil (18 mg, 58%).

[0243] NMR (CDCl₃) δ: 0.90 (m, 2H), 1.06-1.31 (m, 6H), 1.43 (m, 2H),1.51 (s, 3H), 1.60-1.76 (m, 7H), 2.43 (t, 2H), 2.81 (d, 2H), 2.99 (d,2H), 3.01 (s, 3H), 6.98-7.10 (m, 3H), 7.24(m, 1H).

[0244] MS (thermospray): m/z [H³⁰ ] 391.5.; C₂₂H₃₄N₂SO₂+H requires 391.2

EXAMPLE 5

[0245]

[0246] To a solution of3-[3-(3-cyclohexylpropyl)-6-methyl-3-azabicyclo[3.1.0]-hex-6-yl]phenylamine(Preparation 10, 25 mg, 0.08 mmol) in dichloromethane (2 ml) at 0° C.under nitrogen was added pyridine (20 μl, 0.24 mmol) then dropwise over5 minutes ethanesulfonylchloride (25 μl, 34 mg, 0.26 mmol). The mixturewas allowed to warm to room temperature and was stirred for 1.5 h.Further ethanesulfonylchloride (25 μl, 34 mg, 0.26 mmol) was added andthe mixture was stirred for 2 hours. The mixture was concentrated invacuo and the residue was purified by silica (5 g) column chromatographyeluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880).Product-containing fractions were combined and concentrated in vacuo togive the title compound as a pale yellow oil (21 mg, 65%).

[0247] NMR (CDCl₃) δ: 0.90 (m, 2H), 1.06-1.31 (m, 6H), 1.37 (t, 3H),1.44 (m, 2H), 1.51 (s, 3H), 1.60-1.76 (m, 7H), 2.43 (t, 2H), 2.83 (d,21), 2.98 (d, 2H), 3.13 (q, 2H), 6.98-7.10 (m, 3H), 7.24 (t, 1H)

[0248] MS (thermospray): m/z [MH⁺] 405.6.; C₂₃H₃₆N₂SO₂+H requires 405.3

EXAMPLE 6

[0249]

[0250] To a solution of3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation12, 200 mg, 0.735 mmol) in dichloromethane (5 ml) at room temperaturewas added pyridine (0.15 ml, 1.84 mmol) then dropwise over 5 minutesmethane-sulfonylchloride (0.11 ml, 158 mg, 1.38 mmol). The mixture wasstirred for 48 h, concentrated in vacuo and the residue was purified bysilica (10 g) column chromatography eluting with 90:10:1 ethylacetate:methanol:ammonia solution (0.880), then in 80:20:1 ethylacetate:methanol:ammonia solution (0.880). Product-containing fractionswere combined and concentrated in vacuo to give the title compound as apale yellow oil (212 mg, 82%).

[0251] NMR (CDCl₃) δ: 0.90 (t, 3H), 1.28 (m, 6H), 1.47 (s, 3H), 1.54 (m,2H), 1.90 (s, 2H), 2.60 (t, 2H), 2.97 (d, 2H), 3.00 (s, 3H), 3.15 (m,2H), 7.02 (d, 1H), 7.07-7.15 (m, 2H), 7.22 (m, 1H)

[0252] MS (thermospray): m/z [MH³⁰ ] 351.1; C₁₉H₃₀N₂SO₂+H requires 351.2

EXAMPLE 7

[0253]

[0254] To a solution of3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0.]hex-6-yl)phenylamine(Preparation 12, 200 mg, 0.735 mmol) in dichloromethane (5 ml) at roomtemperature was added pyridine (0.15 ml, 1.84 mmol) then dropwise over 5minutes ethanesulfonylchloride (0.131 ml, 177 mg, 1.38 mmol). Themixture was stirred for 48 hours, concentrated in vacuo and the residuewas purified by silica (10 g) column chromatography eluting with ethylacetate then 90:10:1 ethyl acetate:methanol:ammonia solution (0.880).Product-containing fractions were combined and concentrated in vacuo togive the title compound as a pale yellow oil (140 mg, 52%).

[0255] NMR (CDCl₃) δ: 0.90 (t, 3H), 1.28 (m, 6H), 1.34 (t, 3H), 1.47 (s,3H), 1.55 (m, 2H), 1.90 (s, 2H), 2.63 (m, 2H), 2.97 (m, 2H), 3.11 (q,2H), 3.20 (m, 2H), 7.02 (d, 1H) 7.04-7.15 (m, 2H), 7.21 (m, 1H)

[0256] MS (thermospray): m/z [MH⁺] 365.3; C₂₀H₃₂N₂SO₂+H requires 365.2

EXAMPLE 8

[0257]

[0258] To a solution of3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation12, 200 mg, 0.735 mmol), in dichloromethane (5 ml) at room temperaturewas added pyridine (0.15 ml, 1.84 mmol) then dropwise over 5 minutespropanesulfonylchloride (0.16 ml, 202 mg, 1.42 mmol). The mixture wasstirred for 48 hours, concentrated in vacuo and the residue was purifiedby silica (10 g) column chromatography eluting with ethyl acetate then90:10:1 ethyl acetate:methanol:ammonia solution (0.880).Product-containing fractions were combined and concentrated in vacuo togive the title compound as a pale yellow oil (40 mg, 14%).

[0259] NMR (CDCl₃) δ: 0.90 (t, 3H), 1.02 (t, 3H), 1.30 (m, 6H), 1.46 (m,2H), 1.50 (s, 3H), 1.77 (s, 2H), 1.87 (m, 2H), 2.47 (t, 2H), 2.87 (m,2H), 2.93-3.07 (m, 4H), 6.97-7.09 (m, 3H), 7.22 (m, 1H)

[0260] MS (thermospray): m/z [MH⁺] 379.2; C₂₁H₃₄N₂SO₂+H requires 379.2

EXAMPLE 9

[0261]

[0262] To a solution of3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-y1)phenylamine (Preparation12, 220 mg, 0.809 mmol) in dichloromethane (5 ml) at room temperaturewas added pyridine (0.196 ml, 2.42 mmol) then dropwise over 5 minutes3-pyridinesulfonylchloride (198 mg, 1.21 mmol). The mixture was stirredfor 48 hours, concentrated in vacuo and the residue was purified bysilica (10 g) column chromatography eluting with ethyl acetate then90:10:1 ethyl acetate:methanol:ammonia solution (0.880).Product-containing fractions were combined and concentrated in vacuo togive the title compound as a pale orange oil (200 mg, 60%).

[0263] NMR (CDCl₃) δ: 0.89 (t, 3H), 1.30 (m, 6H), 1.40 (s, 3H), 1.52 (m,2H), 1.77 (s, 2H), 2.58 (t, 2H), 2.91 (d, 2H), 3.11 (m, 2H), 6.91-7.04(m, 3H), 7.13 (t, 1H), 7.35 (m, 1H), 8.06 (d, 1H), 8.73 (d, 1H), 8.94(s, 1H)

[0264] MS (thermospray): m/z [MH³⁰ ] 414.2; C₂₃H₃₁N₃SO₂+H requires 414.2

EXAMPLE 10

[0265]

[0266] To a solution of3-[6-ethyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine(Preparation 18, 500 mg, 1.56 mmol) in dichloromethane (20 ml), at 0° C.under nitrogen was added pyridine (0.20 ml, 2.6 mmol) then dropwise over5 minutes methanesulfonylchloride (0.20 ml, 300 mg, 2.6 mmol). Themixture was allowed to warm to room temperature and was stirred for 18h. The mixture was concentrated in vacuo and the residue was purified bysilica (25 g) column chromatography eluting with 70:30:1 ethylacetate:hexane:ammonia solution (0.880). Product-containing fractionswere combined and concentrated in vacuo to give the title compound as apale yellow oil. This was further purified by preparative HPLC(condition 3). Combination and evaporation of pure fractions gave thetitle compound as a white solid (140 mg, 20%).

[0267] NMR (CDCl₃) δ: 0.82 (t, 3H), 1.76 (q, 2H), 1.92 (m, 2H), 2.05 (m,5H), 2.65 (t, 2H), 2.73 (t, 2H), 2.82 (d, 2H), 2.97 (s, 3H), 3.50 (d,2H), 7.05 (m, 3H), 7.14-7.33 (m, 6H)

[0268] MS: m/z [MH⁺] 399.1; C₂₃H₃₀N₂O₂S+H requires 399.2

EXAMPLE 11

[0269]

[0270] To a solution of3-[6-ethyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine(Preparation 18, 500 mg, 1.56 mmol) in dichloromethane (20 ml), at 0° C.under nitrogen was added pyridine (0.20 ml, 2.6 mmol) then dropwise over5 minutes ethanesulfonylchloride (0.20 ml, 0.27 g, 2.1 mmol). Themixture was allowed to warm to room temperature and was stirred for 18hours. The mixture was concentrated in vacuo and the residue waspurified by silica (25 g) column chromatography eluting with 50:50:1ethyl acetate:hexane:ammonia solution (0.880). Product-containingfractions were combined and concentrated in vacuo to give the titlecompound as a pale yellow oil. This was further purified by preparativeHPLC (condition 3). Combination and evaporation of pure fractions gavethe title compound as a white solid (120 mg, 17%).

[0271] NMR (CDCl₃) δ: 0.80 (t, 3H), 1.32 (t, 3H), 1.74 (q, 2H), 1.89 (m,2H), 1.99 (m, 5H), 2.62 (t, 2H), 2.72 (t, 2H), 2.81 (d, 2H), 3.08 (q,2H) 3.43 (d, 2H), 6.97 (d, 1H) 7.07-7.37 (m, 8H)

[0272] MS: m/z [MH⁺] 413.1; C₂₄H₃₂N₂O₂S+H requires 413.2

EXAMPLE 12

[0273]

[0274] To a solution of3-(6-ethyl-3-hexyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation20, 500 mg, 1.56 mmol) in pyridine (5 ml) at 0° C. under nitrogen wasadded dropwise over 5 minutes methanesulfonylchloride (0.20 ml, 0.30 g,2.6 mmol). The mixture was allowed to warm to room temperature and wasstirred for 18 hours. The mixture was concentrated in vacuo and theresidue was purified by silica (25 g) column chromatography eluting with50:50:1 ethyl acetate:hexane:ammonia solution (0.880).Product-containing fractions were combined and concentrated in vacuo togive the title compound as a pale yellow oil (180 mg, 33%).

[0275] NMR (CDCl₃) δ: 0.85 (m, 6H), 1.27 (m, 6H), 1.44 (m, 2H), 1.77 (m,2H), 1.94 (q, 2H). 2.43 (m, 2H), 2.81 (m, 2H), 2.98 (m, 2H), 2.99 (s,3H), 7.00-7.13 (m, 3H), 7.24 (t, 1H),

[0276] MS (electrospray): m/z [MH⁺]; 365.1 C₂₀H₃₂N₂O₂S+H requires 365.2

EXAMPLE 13

[0277]

[0278] To a solution of3-[6-ethyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine(Preparation 20, 500 mg, 1.56 mmol) in pyridine (5 ml), at 0° C. undernitrogen was added dropwise over 5 minutes ethanesulfonylchloride (0.25ml, 0.34 g, 2.6 mmol). The mixture was allowed to warm to roomtemperature and was stirred for 18 hours. The mixture was concentratedin vacuo and the residue was purified by silica (25 g) columnchromatography eluting with 50:50:1 ethyl acetate:hexane:ammoniasolution (0.880). Product-containing fractions were combined andconcentrated in vacuo to give the title compound as a pale yellow oil(150 mg, 31%).

[0279] NMR (CDCL₃) δ: 0.80 (t, 3H), 0.88 (t, 3H), 1.29 (m, 6H), 1.35 (t,3H), 1.44 (m, 2H), 1.77 (m, 2H), 1.93 (q, 2H), 2.45 (t, 2H), 2.82 (m,2H), 2.97 (d, 2H), 3.10 (q, 2H) 7.02-7.29 (m, 4H)

[0280] MS (electrospray): m/z [MH⁺] 379.1; C₂₁H₃₄N₂O₂S+H requires 379.2

EXAMPLE 14

[0281]

[0282] To a solution of3-[3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine(Preparation 25, 34 mg, 0.11 mmol) in dichloromethane (2 ml) at 0° C.under nitrogen was added pyridine (20 μl, 0.24 mmol) thenmethanesulfonylchloride (13 mg, 10 μl, 0.11 mmol). The mixture wasallowed to warm to room temperature and was stirred for 1.5 hours. Themixture was concentrated in vacuo and the residue was purified by silica(5 g) column chromatography eluting with 80:20:1 ethylacetate:hexane:ammonia solution (0.880). Product-containing fractionswere combined and concentrated in vacuo to give the title compound as apale yellow oil (29 mg, 71%).

[0283] NMR (CDCl₃) δ: 1.66 (s, 2H), 1.80 (m, 2H), 2.26 (s, 1H), 2.41 (d,2H), 2.47 (t, 2H), 2.65 (t, 2H), 3.00 (s, 3H), 3.19 (d, 2H), 6.85 (d,1H), 6.90 (s, 1H), 6.98 (d, 1H), 7.20 (m, 4H), 7.29 (m, 2H)

[0284] MS: m/z [MH⁺] 371.0; C₂₁H₂₆N₂O₂S+H requires 371.2

EXAMPLE 15

[0285]

[0286] To a solution of 3-hexyl-6-phenyl-3-azabicyclo[3.1.0]hexan-2-one(Preparation 27, 40 mg, 0.15 mmol) in anhydrous tetrahydrofuran (2 ml)at room temperature under nitrogen, was added dropwise a solution oflithium aluminium hydride 1.0 M in tetrahydrofuran (0.3 ml, 0.3 mmol),then the mixture was heated to 60° C. for 4 hours, cooled and stirred atroom temperature for 64 hours. Water (30 ml) was carefully added, thenthe mixture was extracted with ethyl acetate (2×25 ml). The combinedextracts were washed with water (30 ml), dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by silica (1.5 g) columnchromatography eluting with 80:20:1 ethyl acetate:hexane:ammoniasolution (0.880). Product-containing fractions were combined andconcentrated in vacuo to give the title compound as a pale yellow oil(14 mg, 38%).

[0287] NMR (CDCl₃) δ: 0.90 (t, 3H), 1.30 (m, 6H), 1.44 (m, 2H), 1.65 (s,2H), 2.16 (t, 1H), 2.42 (m, 4H), 3.19 (d, 2H), 7.04 (d, 2H), 7.12 (m,1H), 7.24 (m, 2H)

[0288] MS (APCI): m/z [MH⁺] 244.4; C₁₇H₂₅N+H requires 244.2

EXAMPLE 16

[0289]

[0290] To a solution of3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine(Preparation 8, 200 mg, 0.65 mmol) in pyridine (2 ml) under nitrogen at0° C. was added benzenesulfonylchloride (172 mg, 0.98 mmol), then themixture was stirred at room temperature for 16 hours. Water (5 ml) anddichloromethane (5 ml) were added, and the mixture was stirred for 30minutes. The organic phase was washed further with water (5 ml) for 30minutes, separated, dried (MgSO₄), filtered and concentrated in vacuo.The residue was purified by silica (10 g) column chromatography elutingwith 20:80:1 ethyl acetate:hexane:ammonia solution (0.880), then 50:50:1ethyl acetate:hexane:ammonia solution (0.880). Product-containingfractions were combined and concentrated in vacuo. The residue wasfurther purified by preparative HPLC (condition 4). Combination andevaporation of appropriate fractions gave the title compound as a palebrown solid (5 mg, 2%).

[0291] NMR (CDCl₃) δ: 1.39 (s, 3H), 1.84 (s, 2H), 1.89 (m, 2H), 2.06 (s,3H), 2.65 (m, 4H), 2.90 (d, 2H), 3.23 (br.d, 2H), 6.89 (m, 2H), 6.97 (d,1H), 7.07-7.35 (m, 6H), 7.43 (m, 2H), 7.52 (m, 1H), 7.73 (d, 2H)

[0292] MS (electrospray): m/z [MH⁺] 447.2; C₂₇H₃₀N₂O₂S+H requires 447.2

EXAMPLE 17

[0293]

[0294] To a solution of3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine(Preparation 8, 200 mg, 0.65 mmol) in pyridine (2 ml) under nitrogen at0° C. was added dimethylsulfamoyl chloride (140 mg, 0.98 mmol), then themixture was stirred at room temperature for 16 hours. Water (5 ml) anddichloromethane (5 ml) were added, and the mixture was stirred for 30minutes. The organic phase was washed further with water (5 ml) for 30minutes, separated, dried (MgSO₄), filtered and concentrated in vacuo.The residue was purified by silica (10 g) column chromatography elutingwith ethyl acetate:hexane:ammonia solution (0.880) (20:80:1 then50:50:1). Product-containing fractions were combined and concentrated invacuo. The residue was further purified by preparative HPLC (condition4). Combination and evaporation of appropriate fractions gave the titlecompound as a pale brown solid (7 mg, 3%).

[0295] NMR (CDCl₃) δ: 1.46 (s, 3H), 1.89 (m, 2H), 1.94 (s, 2H), 2.06 (s,3H), 2.66 (m,4H), 2.84 (s, 6H), 2.92 (m, 2H), 3.27 (br.d, 2H), 6.95-7.07(m, 4H), 7.14-7.33 (m, 5H).

[0296] MS (electrospray): m/z [MH⁺] 414.3; C₂₃H₃₁N₃O₂S+H requires 414.2.

EXAMPLE 18

[0297]

[0298] To a solution of3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine(Preparation 8, 200 mg, 0.65 mmol) in pyridine (2 ml) under nitrogen at0° C. was added n-propanesulfonyl chloride (140 mg, 0.98 mmol), then themixture was stirred at room temperature for 16 hours. Water (5 ml) anddichloromethane (5 ml) were added, and the mixture was stirred for 30minutes. The organic phase was washed further with water (5 ml) for 30minutes, separated, dried (MgSO₄), filtered and concentrated in vacuo.The residue was purified by silica (10 g) column chromatography elutingwith ethyl acetate:hexane:ammonia solution (0.880) (20:80:1 then50:50:1). Product-containing fractions were combined and concentrated invacuo. The residue was further purified by preparative HPLC (condition4). Combination and evaporation of appropriate fractions gave the titlecompound as a pale brown solid (11 mg, 4%).

[0299] NMR (CDCl₃) δ: 1.04 (t, 3H), 1.50 (s, 3H), 1.84 (m, 6H), 2.06 (s,3H), 2.54-2.70 (m, 4H), 2.95 (d, 2H), 3.08 (m, 4H), 7.00-7.12 (m, 3H),7.12-7.32 (m, 6H).

[0300] MS (electrospray): m/z [MH⁺ ] 413.3; C₂₄H₃₂N₂O₂S+H requires413.2.

EXAMPLE 19

[0301]

[0302] To a solution of3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine(Preparation 8, 200 mg, 0.65 mmol) in pyridine (2 ml) under nitrogen at0° C. was added 3,5-dimethylisoxazolesulfonyl chloride (190 mg, 0.98mmol), then the mixture was stirred at room temperature for 16 h. Water(5 ml) and dichloromethane (5 ml) were added, and the mixture stirredfor 10 minutes. The organic phase was washed further with water (5 ml),separated, dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was purified by silica (10 g) column chromatography eluting withethyl acetate:hexane:ammonia solution (0.880) (20:80:1 then 60:40:1).Product-containing fractions were combined and concentrated in vacuo.The residue was further purified by preparative HPLC (condition 4).Combination and evaporation of appropriate fractions gave the titlecompound as a pale brown solid (18 mg, 6%).

[0303] NMR (CDCl₃) δ: 1.42 (s, 3H), 1.87 (br.s, 2H), 1.95 (m, 2H), 2.09(s, 3H), 2.25 (s, 3H), 2.43 (s, 3H), 2.55-2.76 (m, 6H), 2.95 (m, 2H),6.91 (d, 1H), 7.00 (s, 1H), 7.05 (d, 1H), 7.13-7.34 (m, 6H)

[0304] MS (electrospray): m/z [MH⁺] 466.3; C₂₆H₃₁N₃O₃S+H requires 466.2

EXAMPLE 20

[0305]

[0306] To a solution of3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine(Preparation 8, 200 mg, 0.65 mmol) in pyridine (2 ml) under nitrogen at0° C. was added 2-methoxy-1-ethanesulfonyl chloride (J. Chem. Soc.,1968, 2895; 155 mg, 0.98 mmol), then the mixture was stirred at roomtemperature for 16 hours. Water (5 ml) and dichloromethane (5 ml) wasadded, and the mixture stirred for 10 minutes. The organic phase waswashed further with water (5 ml), separated, dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by silica (10 g) columnchromatography eluting with ethyl acetate:hexane:ammonia solution(0.880) (20:80:1 then 60:40:1). Product-containing fractions werecombined and concentrated in vacuo. The residue was fiercer purified bypreparative HPLC (condition 4). Combination and evaporation ofappropriate fractions gave the title compound as a pale brown solid (3mg, 1%).

[0307] NMR (CDCl₃) δ: 1.55 (s, 3H), 1.82 (m, 4H), 2.55 (m, 2H), 2.66 (t,2H), 2.80-3.05 (br.m, 4H), 3.23 (t, 2H), 3.42 (s, 3H), 3.84 (t, 2H),7.00-7.33 (m, 9H)

[0308] MS (electrospray): m/z [⁺] 429.3; C₂₄H₃₂N₂O₃S+H requires 429.2

EXAMPLE 21

[0309]

[0310] To a solution of3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine(Preparation 8, 200 mg, 0.65 mmol) in pyridine (2 ml) under nitrogen at0° C. was added α-toluenesulfonyl chloride (186 mg, 0.98 mmol), then themixture was stirred at room temperature for 16 hours. Water (5 ml) anddichloromethane (5 ml) were added and the mixture was stirred for 10minutes. The organic phase was washed further with water (5 ml),separated, dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was purified by silica (10 g) column chromatography eluting withethyl acetate:hexane:ammonia solution (0.880) (20:80:1 then 60:40:1).Product-containing fractions were combined and concentrated in vacuo.The residue was further purified by preparative HPLC (condition 4).Combination and evaporation of appropriate fractions gave the titlecompound as a pale brown solid (3 mg, 1%).

[0311] NMR (CDCl₃) δ: 1.48 (s, 3H), 1.87 (m, 4H), 2.06 (s, 3H), 2.65 (m,4H), 2.96 (d, 2H), 3.16 (br.d, 2H), 4.32 (s, 2H), 6.93-7.06 (m, 3H),7.14-7.40 (m, 11H)

[0312] MS (electrospray): m/z [MH³⁰ ] 461.3; C₂₈H₃₂N₂O₂S+H requires461.2

EXAMPLE 22

[0313]

[0314] To a solution of3-(3-benzyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine(Preparation 30, 1.58 g, 5.68 mmol) in pyridine (10 ml) under nitrogenat 0° C. was added methanesulphonyl chloride (0.66 ml, 8.52 mmol)dropwise to the solution, and the mixture was stirred for 14 hours atroom temperature. The pyridine was evaporated in vacuo and the residuewas partitioned between dichloromethane (50 ml) and dilute aqueoussodium hydrogen carbonate solution (1 M, 50 ml). The layers wereseparated and the organic extract was dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by silica (60 g) columnchromatography eluting with ethyl acetate:hexane (5:95) then ethylacetate:hexane:triethylamine (5:95:0.1 increasing to 80:20:0.1).Appropriate fractions were combined and concentrated in vacuo to givethe title compound as an off-white solid (1 g, 50%).

[0315] mp 117-118° C.

[0316] NMR (CDCl₃) δ: 1.62 (s, 3H), 1.77 (s, 2H), 2.83 (d, 2H), 3.00 (s,3H), 3.07 (d, 2H), 3.68 (s, 2H), 6.27 (br.s, 1H), 7.01 (d, 1H), 7.08 (m,2H), 7.24-7.33 (m, 6H)

[0317] MS (thermospray): m/z [MH⁺] 356.9; C₂₀H₂₄N₂O₂S+H requires 357.2

EXAMPLE 23

[0318]

[0319] To a solution of6-methyl-3-(3-phenylpropyl)-6-[3-(1H-1,2,3-triazol-5-yl)phenyl]-3-azabicyclo[3.1.0]hexan-2-one(Preparation 41, 32 mg, 0.087 mmol) in tetrahydrofuran (2 ml) at roomtemperature was added lithium aluminium hydride (0.43 ml, 0.43 mmol, 1.0M in THF) dropwise over a few minutes. The mixture was stirred at roomtemperature for 6 hours and then quenched by the cautious addition of 2Nsodium hydroxide (0.5 ml) at 0° C. Excess solid sodium hydrogencarbonate and ethyl acetate (5 ml) were then added and the mixture wasstirred rapidly for 30 minutes and then filtered through celite washingwith ethyl acetate. The solvent was evaporated in vacuo and the cruderesidue was purified by silica column chromatography eluting first withhexane:ethyl acetate (1:1) and then hexane:ethyl acetate:ammoniasolution (0.880) (10:90:1) to afford the title compound as a colourlessoil (15.0 mg, 48%).

[0320] NMR (CDCl₃) δ: 1.38 (s, 3H), 1.79-1.90 (m, 4H), 2.50 (t, 2H),2.65 (t, 2H), 2.84 (m, 2H), 3.03 (m, 2H), 7.17-7.40 (m, 7H), 7.60 (d,1H), 7.74 (br. s, 1H), 7.97 (s, 1H)

[0321] MS (thermospray): m/z [MH⁺] 359.4; C₂₃H₂₆N₄+H requires 359.2.

EXAMPLE 24

[0322]

[0323] To a solution of3-hexyl-6-methyl-6-[3-(1H-1,2,3-triazol4-yl)phenyl]-3-azabicyclo[3.1.0]hexan-2-one(Preparation 40, 2.88 mmol) in tetrahydrofuran (25 ml) at 0° C. wasadded lithium aluminium hydride (5.8 ml, 5.76 mmol, 1.0M in THF)dropwise over a few minutes. The mixture was stirred at room temperaturefor 2 hours and then quenched by the cautious addition of 2N sodiumhydroxide (3 ml) at 0° C. Ethyl acetate (15 ml) was then added and themixture was stirred rapidly for 30 minutes and then filtered throughcelite washing with ethyl acetate. The solvent was evaporated in vacuoand the crude residue was purified by silica column chromatographyeluting with hexane:ethyl acetate (1:1) then ethylacetate:methanol:ammonia solution (0.880) (95:5:1) to afford the titlecompound (301 mg, 32% over 2 steps) as a colourless oil.

[0324] NMR (CDCl₃) δ: 0.85-0.95 (m, 3H), 1.25-1.40 (m, 6H), 1.42-1.55(m, 2H), 1.58 (s, 3H), 1.84 (m, 2H), 2.46 (m, 2H), 2.84-3.00 (4H, m),7.23-7.40 (m, 2H), 7.58 (d, 1H), 7.76 (br. s, 1H), 7.98 (s, 1H).

[0325] MS (thermospray): m/z [MH⁺] 325.0; C₂₀H₂₈N₄+H requires 325.2.

EXAMPLE 25

[0326]

[0327] To a solution of3-hexyl-6-methyl-6-[3-(4H-1,2,4-triazol-3-yl)phenyl]-3-azabicyclo[3.1.0]hexan-2-one(Preparation 43, 220 mg, 0.65 mmol) in tetrahydrofuran (5 ml) at roomtemperature was added lithium aluminium hydride (1.3 ml, 1.30 mmol, 1.0Min THF) dropwise over a few minutes. The mixture was then heated underreflux for 2 hours and then cooled to 0° C. 2N sodium hydroxide (1.0 ml)was added cautiously followed by ethyl acetate (10 ml) and the mixturewas stirred rapidly for 30 minutes, then filtered through celite. Thefiltrate was concentrated in vacuo and the residue was purified bysilica column chromatography eluting with ethyl acetate:methanol:ammoniasolution (0.880) (80:20:1) to afford the title compound (190 mg, 90%) asa colourless oil.

[0328] NMR (CDCl₃) δ: 0.82-0.92 (m, 3H), 1.25-1.38 (m, 6H), 1.40 (s,3H), 1.50-1.65 (m, 2H), 1.99 (m, 2H), 2.70 (m, 2H), 2.85 (m, 2H), 3.46(m, 2H), 7.18-7.38 (m, 2H), 7.89-7.92 (m, 2H), 8.18 (s, 1H).

[0329] MS (thermospray): m/z 325.1 [MH³⁰ ]; C_(20 H) ₂₈N₄+H requires325.2

EXAMPLE 26

[0330]

[0331] To a solution of3-hexyl-6-[3-(1H-imidazol-2-yl)phenyl]-6-methyl-3-azabicyclo[3.1.0]-hexan-2-one(Preparation 44, 190 mg, 0.56 mmol) in tetrahydrofuran (5 ml) at roomtemperature was added lithium aluminium hydride (1.1 ml, 1.12 mmol, 1.0M in TBF) dropwise over a few minutes. The mixture was heated underreflux for 1 hour and then cooled to 0° C. 2N sodium hydroxide (1.0 ml)was added cautiously followed by ethyl acetate (10 ml) and the mixturewas stirred rapidly for 30 minutes, then filtered through celite. Thefiltrate was concentrated in vacuo and the residue was purified bysilica column chromatography eluting with ethyl acetate:methanol:ammonia solution (0.880) (90:10:1) to afford the title compound (140 mg,74%) as a white solid.

[0332] NMR (CDCl₃) δ: 0.85-0.95 (m, 3H), 1.24-1.36 (m, 6H), 1.39-1.45(m, 2H), 1.50 (sm 3H), 1.78 (m, 2H), 2.42 (m, 2H), 2.80 (m, 2H), 2.95(m, 2H), 7.10-7.35 (m, 4H), 7.58 (d, 1H), 7.79 (s, 1H)

[0333] MS (thermospray): m/z 324.1 [MH⁺]; C₂₁H₂₉N₃+H requires 324.2

EXAMPLE 27

[0334]

[0335] A solution of2-amino-4-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine(Preparation 48, 112 mg, 0.39 mmol) in formic acid (2.0 ml) was heatedunder reflux for 1 h. The mixture was cooled, diluted with water (3 ml)and the pH adjusted to 10 with 5N sodium hydroxide. The aqueous layerwas extracted with diethyl ether (3×5 ml) and ethyl acetate (2×5ml). Thecombined organic layers were dried (MgSO₄), filtered and the solventremoved in vacuo. The crude residue was purified by silica columnchromatography eluting with ethyl acetate then ethylacetate:methanol:ammonia solution (0.880) (80:20:1) to afford the titlecompound (46 mg, 40%) as a colourless oil.

[0336] NMR (CDCl₃) δ: 0.85-0.95 (m, 3H), 1.22-1.56 (m, 11H),1.83 (m,2H), 2.50 (t, 2H), 2.92-3.00 (m, 4H), 7.20 (d, 1H), 7.50 (s, 1H), 7.56(d, 1H), 8.00 (s, 1H)

[0337] MS (thermospray): m/z 298.2 [MH³⁰ ]; C₁₉H₂₇N₃+H requires 298.2.

EXAMPLE 28

[0338]

[0339] A solution of2-amino-4-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine(Preparation 48, 99.0 mg, 0.345 mmol) in trifluoroacetic acid (2.0 ml)was heated under reflux for 1 hour. The mixture was cooled and thesolvent was removed in vacuo. The residue was suspended in 2N sodiumhydroxide (5 ml) and the aqueous layer was extracted with diethyl ether(3×5 ml). The combined extracts were dried MgSO₄), filtered andconcentrated in vacuo. The crude residue was purified by silica columnchromatography eluting with ethyl acetate to afford the title compound(67 mg, 54%) as a colourless oil.

[0340] NMR (CDCl₃) δ: 0.85-0.95 (m, 3H), 1.25-1.52 (m, 8H), 1.56 (s,3H), 1.83 (m, 2H), 2.50 (t, 2H), 2.92-3.00 (m, 4H), 7.30 (d, 1H), 7.56(s, 1H), 7.62 (d, 1H)

[0341] MS (thermospray): M/Z [MH³⁰ ] 366.4; C₂₀H₂₆F₃N₃+H requires 366.2

EXAMPLE 29

[0342]

[0343] A solution of3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation12, 0.10 g, 0.37 mmol) in pyridine (5 ml) cooled at 0° C. was treatedwith 2-methylbenzenesulfonyl chloride (0.08 g, 0.44 mmol). The reactionmixture was stirred at room temperature for 3 h, water (30 ml) was addedand the product was extracted with diethyl ether (30 ml×3). The combinedorganic extracts were dried (Na₂SO₄) and then concentrated in vacuo. Thecrude products were purified by preparative HPLC (condition 5) to givethe acetate salt as a brown gum, (30 mg, 20%).

[0344] NMR (CDCl₃, selected data for the acetate salt): 0.9 (m, 3H),1.1-1.2 (m, 9H), 1.6 (m, 2H), 2.0 (m, 2H), 2.6 (s, 3H), 2.9 (m, 2H), 3.0(m, 2H), 3.55 (m, 2H), 6.8-7.9 (m, 8H).

[0345] MS (ES): M/Z (MH+)427.3; C₂₅H₃₄N₂O₂S +H requires 427.2.

EXAMPLE 30

[0346]

[0347] The title compound was prepared by the method of Example 29substituting 2-methylbenzenesulfonyl chloride with2-chlorobenzenesulfonyl chloride (90 mg, 0.44 mmol) to give a lightbrown gum (30 mg, 18%).

[0348] NMR (CDCl₃, selected data for the acetate salt): 0.9 (m, 3H),1.1-1.2 (m, 9H), 1.6 (m, 2H), 2.8 (m, 2H), 3.0 (m, 2H), 3.4 (m, 2H),6.85-6.95 (m, 2H), 7.05 (s, 1H), 7.1 (t, 1H), 7.4 m, 1H), 7.5-7.6 (m,2H), 8.0 (d, 1H).

[0349] MS (ES): M/Z (MH⁺) 447.3; C₂₄H₃₁ClN₂O₂S+H requires 447.2.

EXAMPLE 31

[0350]

[0351] A solution of3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation12, 0.10 g, 0.37 mmol) in pyridine (5 ml) cooled at 0° C. was treatedwith 4-chlorobenzenesulfonyl chloride (90 mg, 0.44 mmol). The reactionmixture was stirred at room temperature for 3 h, water (30 ml) was addedand the product was extracted with diethyl ether (30 ml×3). The combinedorganic extracts were dried (Na₂SO₄) and then concentrated in vacuo. Thecrude products were purified by preparative HPLC (condition 5). Theacetate salt obtained was basified with saturated aqueous sodiumhydrogen carbonate solution (20 ml) and extracted with dichloromethane(2×20 ml). The combined organic extracts were dried Na₂SO₄) andconcentrated in vacuo to give a colourless oil, (20 mg, 13%).

[0352] NMR (CDCl₃, selected data for the free base): 0.85 (m, 3H),1.2-1.35 (m, 6H), 1.4 (s, 3H), 1.7 (m, 2H), 2.5 (m, 2H), 2.9 (m, 2H),6.8 (d, 1H), 6.9 (s, 1H), 7.0 (d, 1H), 7.1(t, 1H), 7.4 (d, 2H), 7.65 (d,2H).

[0353] MS (ES): M/Z (MH⁺) 447.3; C₂₄H₃₁ClN₂O₂S+H requires 447.2.

EXAMPLE 32

[0354]

[0355] The title compound was prepared by the method of Example 31substituting 4-chlorobenzenesulfonyl chloride with2-[(chlorosulfonyl)amino]propane (Preparation 49, 70 mg, 0.44 mmol) togive a colourless oil (20 mg, 14 %).

[0356] NMR (CDCl₃, selected data for the acetate salt): 0.85 (m, 3H),1.15 (d, 6H), 1.2-1.4 (m, 9H), 1.4 (m, 2H), 1.8 (m, 2H), 2.4 (m, 2H),2.8 (m, 2H), 2.95 (m, 2H), 3.55 (m, 1H), 4.25 (br, 1H), 6.9-7.05 (m,3H), 7.2, t, 1H).

[0357] MS (ES): M/Z (MH³⁰ ) 394.3; C₂₁H₃₅N₃O₂S+H requires 394.3.

EXAMPLE 33

[0358]

[0359] The title compound was prepared by the method of Example 31substituting 4-chlorobenzenesulfonyl chloride with 1-butanesulfonylchloride (69 mg, 0.44 mmol) to give a colourless oil (20 mg, 14%).

[0360] MS (ES): M/Z (MH⁺) 393.3; C₂₂H₃₆N₂O₂S+H requires 393.3.

[0361] Analytical HPLC purity: 95%, retention time 17.6 min (condition6).

EXAMPLE 34

[0362]

[0363] A solution of3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation12, 0.10 g, 0.37 mmol) in pyridine (5 ml) cooled at 0° C. was treatedwith 1-methyl-1H-imidazole-4-sulfonyl chloride (0.08 g, 0.44 mmol). Thereaction mixture was stirred at room temperature for 3 h, water (30 ml)was added and the product was extracted with dichloromethane (30 ml×3).The combined organic extracts were dried (Na₂SO₄) and then concentratedin vacuo. The crude products were purified by preparative HPLC(condition 5). The acetate salt obtained was basified with saturatedaqueous sodium hydrogen carbonate solution (20 ml) and extracted withdichloromethane (2×20 ml). The combined organic extracts were dried(Na₂SO₄) and concentrated in vacuo to give an off-white solid, (30 mg,20%).

[0364] NMR (CDCl₃, selected data for the free base): 0.9 (t, 3H),1.2-1.35 (m, 6H), 1.4 (s, 3H), 1.65 (m, 2H), 2.45 (m, 2H), 2.8 (m, 2H),2.95 (d, 2H), 3.65 (s, 3H), 6.9-7.2 (m, 4H), 7.3 (s, 1H), 7.45 (s, 1H).

[0365] MS (ES): M/Z (MH⁺⁾ 417.0; C₂₂H₃₂N₄O₂S+H requires 417.2.

EXAMPLE 35

[0366]

[0367] A solution of3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation12, 0.10 g, 0.37 mmol) in pyridine (5 ml) cooled at 0° C. was treatedwith 2,1,3-benzoxadiazole-4-sulfonyl chloride (0.1 g, 0.44 mmol). Thereaction mixture was stirred at room temperature for 3 h, water (30 ml)was added and the product was extracted with diethyl ether (30 ml×3).The combined organic extracts were dried (Na₂SO₄) and then concentratedin vacuo. The crude products were purified by preparative BPLC(condition 1), to give the acetate salt as an off-white gum (14 mg, 8%).

[0368] NMR (CDCl₃, selected data for the acetate salt): 0.85 (t, 3H),1.2-1.30 (m, 6H), 1.35 (s, 3H), 1.5 (m, 2H), 1.6 (m, 2H), 2.45 (m, 2H),2.8-2.95 (m, 4H), 3.65 (s, 3H), 3.7 (br, 1H), 6.8 (d, 1H), 6.85-6.95 (m,2H), 7.0 (t, 1H), 7.45 (m, 1H), 7.9-8.1 (m, 2H).

[0369] MS (ES): M/Z (MH⁺) 455.3; C₂₄H₃₀N₄O₃S+H requires 455.2.

EXAMPLE 36

[0370]

[0371] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate solution (63 mg, 0.75 mmol) and1-bromo-5-methyl hexane (37 mg, 0.20 mmol). The reaction mixture washeated for 30 h at 50° C., and then cooled to room temperature. Diethylether (5 ml) was added followed by water (10 ml), the organic extractswere separated and the aqueous layer was washed further with diethylether (2×5 ml). The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo. The residues were purified by flashchromatography on an SPE cartridge containing silica gel (5 g) elutingwith dichloromethane:ethanol:0.880 ammonia (200:8:1) to give the productas an oil (32 mg, 49%).

[0372] NMR (CDCl₃, selected data for the free base): 0.85 (d, 6H),1.15-1.6 (m, 8H), 1.5 (s, 3H) 1.75 (m, 2H), 2.5 (m, 2H), 2.8-3.0 (m,4H), 3.0 (s, 3H), 7.0-7.1 (m, 3H), 7.2 (t, 1H).

[0373] MS (ES): M/Z (MH⁺) 365.2; C₂₀H₃₂N₂O₂S+H requires 365.2.

EXAMPLE 37

[0374]

[0375] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 68 mg, 0.23 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate solution (76 mg, 0.90 mmol) and(2-bromoethyl)benzene (46 mg, 0.25 mmol). The reaction mixture washeated for 17 h at 50° C., and then cooled to room temperature. Diethylether (5 ml) was added followed by water (10 ml), the organic extractswere separated and the aqueous layer was washed further with diethylether (3×6 ml). The combined organic extracts were dried over (Na₂SO₄)and concentrated in vacuo. The residues were purified by flashchromatography on an SPE cartridge containing silica gel (5 g) elutingwith dichloromethane:ethanol:0.880 ammonia (200:8:1) to give the productas a pale yellow oil (35 mg, 41%).

[0376] NMR (CDCl₃, selected data for the free base): 1.6 (s, 3H), 1.8(m, 2H), 2.75-2.85 (m, 4H), 2.9-3.1 (m, 7H), 6.9-7.1 (m, 3H), 7.15-7.3(m, 6H).

[0377] MS (ES): M/Z (MH⁺): 371.0, C₂₁H₂₆N₂O₂S+H requires 371.2.

EXAMPLE 38

[0378]

[0379] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate solution (63 mg, 0.75 mmol) and2-(bromoethoxy)benzene (42 mg, 0.20 mmol). The reaction mixture washeated for 30 h at 50° C., and then cooled to room temperature. Diethylether (5 ml) was added followed by water (10 ml), the organic extractswere separated and the aqueous layer was washed further with diethylether (2×5 ml). The combined organic extracts were dried over (Na₂SO₄)and concentrated in vacuo. The residues were purified by flashchromatography on an SPE cartridge containing silica gel (5 g) elutingwith dichloromethane:ethanol:0.880 ammonia (200:8:1) to give the productas an oil (41 mg, 59%).

[0380] NMR (CDCl₃, selected data for the free base): 1.5 (s, 3H), 1.8(m, 2H), 2.9-3.1 (m, 9H), 4.05 (m, 2H), 6.85-6.95 (m, 3H), 7.0-7.1 (m,3H), 7.2-7.35 (m, 3H).

[0381] MS (ES): M/Z (MH⁺)387.3; C₂₁H₂₆N₂O₃S+H requires 387.2.

EXAMPLE 39

[0382]

[0383] A solution of ethyl2-{[3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)anilino]sulfonyl}acetate(Example 41, 0.13 g, 0.38 mmol) in ammonia (2M in methanol, 3.0 ml, 1.5mmol) was heated to 60° C. for 12 h in a sealed tube. The mixture wascooled, concentrated in vacuo and then purified by chromatography onsilica gel eluting with methanol:ethyl acetate (2:98) to give theproduct as a pale yellow foam (80 mg, 53%).

[0384] NMR (CDCl₃, selected data for the free base): 0.9 (m, 3H),1.25-1.4 (m, 6H), 1.4-1.5 (m, 5H), 1.8 (m, 2H), 2.5 (m, 2H), 2.85-3.0(m, 4H), 3.85 (s, 2H), 5.8 (br, 1H), 7.1-7.25 (m, 4H).

[0385] MS (ES): M/Z (MH⁺) 394.4; C₂₀H₃₁N₃O₃S+H requires 394.2.

EXAMPLE 40

[0386]

[0387] To a solution of3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation12, 0.11 g, 0.40 mmol) in dichloromethane (1.5 ml) was added pyridine(64 mg) in dichloromethane (0.75 ml) and 2-methoxy-1-ethanesulfonylchloride (J. F. King, J. Y. L. Lam, S. Kronieczny, J. Am. Chem. Soc.,1992, 114 (5), 1743; 0.96 g, 0.60 mmol). The reaction mixture wasstirred at room temperature for 16 h and then concentrated in vacuo. Thecrude residue was purified by chromatography on silica gel eluting withethyl acetate:2M ammonia in methanol (99:1).

[0388] NMR (CDCl₃, selected data for the free base): 0.9 (m, 3H),1.2-1.4 (m, 6H), 1.45 (m, 2H), 1.5 (s, 3H), 1.8 (m, 2H), 2.4 (m, 2H),2.8 (m, 2H), 3.0 (m, 2H), 3.2 (m, 2H), 3.4 (s, 3H), 3.8 (m, 2H),6.95-7.15 (m, 3H), 7.25 (m, 1H).

[0389] MS (ES): M/Z (MH⁺) 395.2; C₂₁H₃₄N₂O₃S+H requires 395.2

EXAMPLE 41

[0390]

[0391] To a solution of3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation12, 0.50 g, 1.84 mmol) in dichloromethane (5.0 ml) was added pyridine(0.27 ml) in dichloromethane (2.5 ml) and ethyl(2-chlorosulfonyl)acetate (J. E. Oliver, A. B. DeMilo, Synthesis, 1975,321, 0.48 g, 2.5 mmol). The reaction mixture was stirred at roomtemperature for 8 h, saturated aqueous sodium hydrogen carbonatesolution (10 ml) was added, the organic extracts were separated and theaqueous layer was further extracted with dichloromethane (2×10 ml). Thecombined organic layers were dried (MgSO₄) and concentrated in vacuo.The crude extracts were purified by chromatography on silica gel elutingwith ethyl acetate:hexane (10:1) to give a colourless oil whichsolidified upon cooling (0.70 g, 91%).

[0392] NMR (CDCl₃, selected data for the free base): 0.85 (m, 3H),1.2-1.4 (m, 9H), 1.4 (m, 2H), 1.5 (s, 3H), 1.7 (m, 2H), 2.4 (m, 2H), 2.8(m, 2H), 3.0 (m, 2H), 3.85 (s, 2H), 4.25 (q, 2H), 7.05-7.2 (m, 4H).

[0393] MS (ES): M/Z (MH⁺) 423.2; C₂₂H₃₄N₂O₄S+H requires 423.2

EXAMPLE 42

[0394]

[0395] A solution of3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation12, 0.75 g, 0.28 mmol) in pyridine (1.5 ml) cooled at 0° C was treatedwith 2-propanesulfonyl chloride (0.05 g, 0.33 mmol). The reactionmixture was stirred at room temperature for 16 h. The reaction mixturewas concentrated in vacuo and the crude red residue was purified bychromatography on silica gel (5 g) eluting with hexane:ethylacetate:0.880 ammonia (50:50:0.5) to give the product as a light greengum (15 mg, 14%).

[0396] NMR (CDCl₃, selected data for the free base): 0.9 (t, 3H),1.05-1.15 (m, 12H), 1.2-1.35 (m, 5H), 1.8 (m, 2H), 2.5 (m, 2H), 2.8 (m,2H), 3.0 (m, 2H), 3.2 (m, 1H), 6.95-7.1 (m, 2H), 7.15-7.25 (m, 2H).

[0397] MS (ES): M/Z (MH⁺) 379.4; C₂₁H₃₄N₂O₂S+H requires 379.2.

EXAMPLE 43

[0398]

[0399] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate solution (63 mg, 0.75 mmol) and6-bromohexanenitrile (36 mg, 0.20 mmol). The reaction mixture was heatedfor 30 h at 50° C., and then cooled to room temperature. Diethyl ether(5 ml) was added followed by water (10 ml), the organic extracts wereseparated and the aqueous layer was washed further with diethyl ether(2×5 ml). The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo. The residues were purified by flashchromatography on an SPE cartridge containing silica gel (5 g) elutingwith dichloromethane:ethanol 0.880 ammonia (200:8:1) to give the productas an oil (32 mg, 49%).

[0400] NMR (CDCl₃, selected data for the free base):1.4-1.6 (m, 7H), 1.7(m, 2H), 1.8 (m, 2H), 2.3 (m, 2H), 2.5 (m, 2H), 2.8 (m, 2H), 2.9-3.0 (m,5H), 6.95-7.1 (m, 3H), 7.25 (t, 1H).

[0401] MS (ES): M/Z (MH⁺) 362.2; C₁₉H₂₇N₃O₂S+H requires 362.2.

EXAMPLE 44

[0402]

[0403] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate solution (63 mg, 0.75 mmol) and4-bromo-1,1,1-trifluorobutane (40 mg, 0.20 mmol). The reaction mixturewas heated for 30 h at 50° C., before addition of further4-bromo-1,1,1-trifluorobutane (20 mg, 0.10 mmol). The reaction mixturewas cooled to room temperature, diethyl ether (5 ml) was added followedby water (10 ml), the organic extracts were separated and the aqueouslayer was washed further with diethyl ether (2×5 ml). The combinedorganic extracts were dried (Na₂SO₄) and concentrated in vacuo. Theresidues were purified by flash chromatography on an SPE cartridgecontaining silica gel (5 g) eluting with dichloromethane:ethanol:0.880ammonia (200:8:1) to give the product as an oil (29 mg, 43%).

[0404] NMR (CDCl₃, selected data for the free base): 1.5 (s, 3H),1.65-2.85 (m, 4H), 2.15 (m, 2H), 2.6 (m, 2H), 2.8-3.1 (m, 4H), 3.0 (s,3H), 7.0-7.15 (m, 3H), 7.2 (m, 1H).

[0405] MS (ES): M/Z (MH⁺) 377.3; C₁₇H₂₃F₃N₂O₂S+H requires 377.2.

EXAMPLE 45

[0406]

[0407] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.18 mmol) in N,N-dimethylformamide 2 ml) wasadded sodium hydrogen carbonate solution (63 mg, 0.75 mmol) and3-phenoxypropyl bromide (45 mg, 0.20 mmol). The reaction mixture washeated for 30 h at 50° C., and then cooled to room temperature. Diethylether (5 ml) was added followed by water (10 ml), the organic extractswere separated and the aqueous layer was washed further with diethylether (2×5 ml). The combined organic extracts were dried over (Na₂SO₄)and concentrated in vacuo. The residues were purified by flashchromatography on an SPE cartridge containing silica gel (5 g) elutingwith dichloromethane:ethanol:0.880 ammonia (200:81) to give the productas an oil (40 mg, 55%).

[0408] NMR (CDCl₃, selected data for the free base): 1.55 (s, 3H), 1.8(m, 2H), 1.95 (m, 2H), 2.65 (m, 2H), 2.9 (m, 2H), 3.0 (s, 3H), 3.05 (m,2H), 4.0 (t, 2H), 6.85-6.95 (m, 3H), 7.01-7.1 (m, 3), 7.2-7.35 (m, 3H).

[0409] MS (ES): M/Z (MH⁺) 401.3; C₂₂H₂₈N₂O₃S+H requires 401.2.

EXAMPLE 46

[0410]

[0411] A solution of3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation12, 0.10 g, 0.37 mmol) in pyridine (10 ml) cooled at 0C was treated with5-isoquinolinesulfonyl chloride (0.10 g, 0.44 mmol). The reactionmixture was stirred at room temperature for 16 h before addition of more5-isoquinolinesulfonyl chloride (0.05 g, 0.22 mmol). The reactionmixture was concentrated in vacuo and the crude red residue wasdissolved in dichloromethane (20 ml) and washed with saturated aqueoussodium hydrogen carbonate solution (20 ml), the aqueous phase wasextracted with dichloromethane (2×20 ml). The combined organic extractswere dried (Na₂SO₄), filtered and concentrated in vacuo. The crudeproduct was purified by chromatography on silica gel (5 g) eluting withhexane:ethyl acetate:0.88 ammonia (30:70:0.5 and then 0:100:0.5) to givethe product as a yellow gum (90 mg, 52%).

[0412] NMR (CDCl₃, selected data for the free base): 0.85 (m, 3H),1.2-1.35 (m, 9H), 1.3-1.6 (m, 4H), 2.45 (m, 2H), 2.8-3.0 (br, 3H), 6.75(d, 1H), 6.8 (s, 1H), 6.9 (d, 1H), 7.0 (t, 1H), 7.6 (t, 1H), 8.15 (d,1H), 8.3-8.4 (m, 2H), 8.6 (m, 1H), 9.3 (m, 1H).

[0413] MS (ES): M/Z (MH⁺) 464.2; C₂₇H₃₃N₃O₂S+H requires 464.2.

EXAMPLE 47

[0414]

[0415] To a stirred solution of3-(3-hexyl-6-isopropyl-3-azabicyclo[3.1.0]hex-6-yl)aniline (Preparation61, 0.17 g, 0.57 mmol) in dichloromethane (5 ml) under nitrogen wasadded pyridine (0.07 ml, 0.91 mmol) and the reaction mixture was cooledto −5° C. Methanesulfonyl chloride (0.05 ml, 0.68 mmol) was addeddropwise so that the internal temperature was maintained below −2° C.The reaction mixture was stirred for 3 h and then treated with water (40ml) and extracted with dichloromethane (3×50 ml). The combined organicextracts were washed with brine (50 ml), dried (Na₂SO₄) and concentratedin vacuo to give an amber oil. The crude product was purified bychromatography on a Biotage Flash12M™ cartridge packed with silica gel(8 g), the product was eluted with ethyl acetate:0.880 ammonia (99:1) togive the purified product (0.12 g, 56%).

[0416] NMR (CDCl₃, selected data for the free base): 0.8 (d, 6H), 0.9(m, 3H), 1.2-1.4 (m, 6H), 2.4 (m, 2H), 2.8 (m, 2H), 2.9 (m, 2H), 3.0 (s,3H), 7.0-7.25 (m, 4H),

[0417] MS (ES): M/Z (MH⁺) 379.0; C₂₁H₃₄N₂O₂S+H requires 379.2.

EXAMPLE 48

[0418]

[0419] To a stirred solution of3-(3-hexyl-6-propyl-3-azabicyclo[3.1.0]hex-6-yl)aniline (Preparation 66,1.0 g, 3.32 mmol) in dichloromethane (52 ml) under nitrogen was addedpyridine (53 μl, 6.56 mmol) and the reaction mixture was cooled to 0° C.Methanesulfonyl chloride (280 μl, 3.61 mmol) was added dropwise and thenthe reaction mixture was stirred at room temperature for 16 h. The cruderesidue was dissolved in dichloromethane:2M ammonia solution in methanol(80:20), filtered through a pad of silica gel and then through a syringefilter and concentrated in vacuo to give the hydrochloride salt whichwas then treated with 0.880 ammonia:water (1:3) and extracted withdiethyl ether. The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo to give an orange oil (1.18 g, 94%).

[0420] NMR (CDCl₃, selected data for the free base): 0.8-1.0 (m, 6H),1.2-1.4 (m, 8H), 1.45 (m, 2H), 1.8 (m, 2H), 1.9 (m, 2H), 2.5 (m, 2H),2.8 (m, 2H), 2.9-3.0 (m, 5) 1.0-7.1 (m, 3H), 7.2 (t, 1H).

[0421] MS (APCI): M/Z (MH⁺) 379.1; C₂₁H₃₄N₂O₂S+H requires 379.2.

EXAMPLE 49

[0422]

[0423]3-Hexyl-6-methyl-6-[3-(2-pyridinyl)phenyl]-3-azabicyclo[3.1.0]hexan-2-one(Preparation 68, 33 mg, 0.09 mmol) was dissolved in tetrahydrofuran (10ml) at 0° C. Lithium aluminium hydride (1M in tetrahydrofuran, 0.2 ml,0.2 mmol) was added under nitrogen and then the reaction mixture wasstirred at room temperature for 16 h. The reaction mixture was quenchedby adding aqueous sodium hydroxide solution (2N, 0.4 ml), followed bysolid sodium hydrogen carbonate and ethyl acetate. The reaction mixturewas stirred vigorously and then filtered through Celite®. The filtratewas concentrated in vacuo and the residue was chromatographed on silicagel eluting with ethyl acetate to give the product as a colourless oil(13 mg, 41%).

[0424] NMR (CDCl₃, selected data for the free base): 0.9 (m, 3H),1.2-1.4 (m, 6H), 1.55-1.65 (m, 5H), 1.8 (m, 2H), 2.45 (m, 2H), 2.8 (m,2H), 3.0 (m, 2H), 7.2-7.4 (m, 4H), 7.7-7.8 (m, 2H), 7.9 (m, 1H), 8.7 (m,1H).

[0425] MS (TSP): M/Z (MH⁺) 335.6; C₂₃H₃₀N₂+H requires 335.2.

EXAMPLE 50

[0426]

[0427]3-Hexyl-6-methyl-6-[3-(2-thienyl)phenyl]-3-azabicyclo[3.1.0]hexan-2-one(Preparation 69, 64 mg, 0.19 mmol) was dissolved in tetrahydrofuran (20ml) at 0° C. Lithium aluminium hydride (1M in tetrahydrofuran, 0.4 ml,0.4 mmol) was added under nitrogen and then the reaction mixture wasstirred at room temperature for 16 h. The reaction mixture was quenchedby adding aqueous sodium hydroxide solution (2N, 0.8 ml), followed bysolid sodium hydrogen carbonate and ethyl acetate. The reaction mixturewas stirred vigorously and then filtered through Celite®. The filtratewas concentrated in vacuo and the residue chromatographed on silica geleluting the product with hexane:ethyl acetate (2:1) as a colourless oil(66 mg, 64%).

[0428] NMR (CDCl₃, selected data for the free base): 0.8 (m, 3H),1.2-1.4 (m, 6H), 1.45 (m, 2H), 1.55 (s, 3H), 1.8 (m, 2H), 2.45 (m, 2H),2.8 (m, 2H), 3.0 (m, 2H), 7.15 (d, 1H), 7.2-7.35 (m, 3H), 7.4 (d, 1H),7.5 (s, 1H).

[0429] MS (TSP): M/Z (MH⁺) 340.3; C₂₂H₂₉NS+H requires 340.2.

EXAMPLE 51

[0430]

[0431] A solution of sodium nitrite (97 mg, 1.4 mmol) dissolved in water(2 ml) was added to3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation12, 0.17 g, 0.61 mmol) dissolved in aqueous hydrochloric acid (2.0 M, 2ml) over a few minutes at 0° C. After 30 min at 0° C., the reactionmixture was added to copper (I) chloride (1.57 g, 15.8 mmol) inconcentrated hydrochloric acid (4.0 ml). After stirring the reactionmixture at room temperature for 45 min, the reaction mixture was heatedto 90° C. for 5 min. The reaction mixture was poured cautiously on tosolid, pre-wetted sodium hydrogen carbonate and the product wasextracted firstly with diethyl ether and then ethyl acetate. Thecombined organic extracts were dried (MgSO₄) and then concentrated invacuo. The crude residue was purified by chromatography on silica geleluting with hexane:ethyl acetate (8:1) to give the product (69 mg,39%).

[0432] NMR (CDCl₃, selected data for the free base): 0.9 (m, 3H),1.2-1.4 (m, 6H), 1.4 (m, 2H), 1.5 (m, 3H), 1.75 (m, 2H), 2.4 (m, 2H),2.75 (m, 2H), 2.95 (m, 2H), 7.0-7.3 (m, 4H).

[0433] MS (TSP): M/Z (MH⁺) 292.2; C₁₈H₂₆ClN+H requires 292.2.

EXAMPLE 52

[0434]

[0435] To a solution of3-hexyl-6-[3-(1H-imidazol-5-yl)phenyl]-6-methyl-3-azabicyclo[3.1.0]hexan-2-one(Preparation 75, 21 mg, 62.3 lmol) in tetrahydrofuran (1.5 ml) at roomtemperature was added lithium aluminium hydride (1.0 M intetrahydrofuran, 0.12 ml, 0.12 mmol) over 2 min. The reaction mixturewas stirred at room temperature for 30 min and then heated under refluxfor 2 h before cooling to room temperature. Aqueous sodium hydroxidesolution (1 M, a few drops) and excess ethyl acetate were added followedby solid sodium hydrogen carbonate. The reaction mixture was stirredrapidly for 1 h before filtering. The mother liquor was concentrated invacuo and the crude residue was chromatographed on silica gel elutingwith ethyl acetate and then ethyl acetate:methanol (80:20) to give theproduct as a colourless semi-solid (15 mg, 75%).

[0436] NMR (CDCl₃, selected data for the free base: 0.85 (m, 3H),1.2-1.4 (m, 6H), 1.45 (m, 2H), 1.5 (s, 3H), 1.8 (m, 2H), 2.5 (m, 2H),2.85-3.0 (m, 4H), 7.15 (d, 1H), 7.2-7.25 (m, 2H), 7.5 (m, 1H), 7.65 (m,1H), 7.7 (s, 1H).

[0437] MS (ES): M/Z (MH⁺) 324.3; C₂₁H₂₉N₃+H requires 324.2.

EXAMPLE 53

[0438]

[0439] To a solution of3-benzyl-6-methyl-6-(3-pyridinyl)-3-azabicyclo[3.1.0]hexane-2,4-dione,(Preparation 77, 1.0 g, 3.42 mmol) in tetrahydrofuran (50 ml), was addedlithium aluminium hydride (1.0 M in tetrahydrofuran, 13.7 ml, 14.0mmol). The reaction mixture was heated under reflux for 2 h, cooled toroom temperature for 16 h and then refluxed for a further 3 h. Thereaction mixture was cooled to room temperature, aqueous sodiumhydroxide solution (5M, 14 ml) was added followed by ethyl acetate (20ml). The reaction mixture was filtered through Celite® and the filtratewas concentrated in vacuo. The crude residue was purified bychromatography on silica gel, eluting withmethanol:dichloromethane:0.880 ammonia (2:97:1 and then 5:94:1) to givethe product (0.30 g, 33%).

[0440] NMR (CDCl₃, selected data for the free base): 1.2 (s, 3H), 1.4(m, 2H), 2.8 (s, 2H), 3.4 (s, 2H), 4.6 (s, 2H), 7.2-7.3 (m, 4H),7.4-7.45 (m, 2H), 7.6 (m, 1H), 8.5-8.6 (m, 2H).

[0441] MS (TSP): M/Z (MH⁺) 265.1; C₁₃H₂₀N₂+H requires 265.2.

EXAMPLE 54

[0442]

[0443] To a solution of3-hexyl-6-methyl-6-(3-pyridinyl)-3-azabicyclo[3.1.0]hexane-2,4-dione(Preparation 78, 0.22 g, 0.78 mmol) in tetrahydrofuran (15 ml) was addedlithium aluminium hydride (1.0 M in tetrahydrofuran, 1.6 ml, 1.6 mmol).The reaction mixture was heated under reflux for 3 h before cooling toroom temperature and stirring for 16 h. Water (2 ml) was added followedby ethyl acetate (5 ml). The reaction mixture was filtered throughCelite® and concentrated in vacuo. The crude residue was purified onsilica gel eluting with dichloromethane:methanol:0.880 ammonia (99:0:1and then 89:10:1) to give the pure product (0.13 g, 64%).

[0444] NMR (CDCl₃, selected data for the free base): 0.9 (m, 3H),1.2-1.4 (m, 6H), 1.5 (m, 2H), 1.55 (s, 3H), 1.8 (m, 2H), 2.5 (m, 2H),2.85 (m, 2H), 3.05 (m, 2H), 7.15 (m, 1H), 7.55 (m, 1H), 8.4 (m, 1H),8.55 (m, 1H).

[0445] MS (TSP): M/Z (MH³⁰ ) 259.9; C₁₇H₂₆N₂+H requires 259.2.

EXAMPLE 55

[0446]

[0447] To6-methyl-3-(3-phenylpropyl)-6-(3-pyridinyl)-3-azabicyclo[3.1.0]hexane-2,4-dione(Preparation 79, 0.23 g, 0.72 mmol) dissolved in tetrahydrofuran (15 ml)was added lithium aluminium hydride (1.0 M in tetrahydrofuran, 1.4 ml,1.4 mmol). The reaction mixture was heated under reflux for 4 h beforecooling to room temperature and adding water (2 ml) and ethyl acetate (5ml). The reaction mixture was filtered through Celite® and concentratedin vacuo. The crude residue was purified on silica gel (10 g) elutingwith dichloromethane:methanol:0.880 ammonia (99:0:1 and then 89:10:1) togive the pure product (0.2 g, 95%).

[0448] NMR (CDC₃, selected data for the free base): 1.6 (s, 3H), 1.75(m, 4H), 2.45 (m, 2H), 2.65 (m, 2H), 2.8 (m, 2H), 3.1 (m, 2H), 7.05-7.3(m, 6H), 7.5 (m, 1H), 8.4 (m, 1H), 8.5 (s, 1H).

[0449] MS (TSP): M/Z (MH³⁰ ) 293.0; C₂₀H₂₄N₂+H requires 293.2.

EXAMPLE 56

[0450]

[0451] To 3-(3-allyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)aniline(Preparation 52, 8.5 g, 37.2 mmol) dissolved in pyridine (70 ml) at 0°C. was added methanesulphonyl chloride (4.32 ml, 55.8 mmol) dropwiseover 20 min. The reaction mixture was allowed to stir for 16 h and wasthen quenched with ice (5 g). The reaction mixture was concentrated invacuo and the residue was dissolved in dichloromethane and washed withsaturated aqueous sodium hydrogen carbonate solution, followed by water.The organic extracts were concentrated in vacuo and then purified byflash chromatography on silica gel, eluting with ethylacetate:dichloromethane: 2N ammonia in methanol (30:69:1). The productwas obtained as a viscous brown oil (7.7 g, 68%).

[0452] NMR (CDCl₃, selected data for the free base): 1.5 (s, 3H), 1.8(m, 2H), 2.8 (m, 2H), 2.95-3.05 (m, 5H), 3.1 (m, 2H), 5.05 (m, 1H), 5.2(m, 1H), 5.85 (m, 1H), 7.0-7.1 (3H), 6.2 (t, 1H).

[0453] MS (ES): M/Z (MH⁺) 307.0; C₁₆H₂₂N₂O₂S+H requires 307.1.

EXAMPLE 57

[0454]

[0455] To a solution of ethyl2-1{[3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)anilino]sulfonyl}acetate(Example 41, 0.17 g, 0.43 mmol) in diethyl ether (6.5 ml) was addedlithium borohydride (20 mg, 0.91 mmol) followed by methanol (37 l) indiethyl ether (0.5 ml). The reaction mixture was stirred at roomtemperature for 5 h and then quenched with saturated aqueous sodiumhydrogen carbonate solution. The organic extracts were extracted withethyl acetate, dried (MgSO₄) and then concentrated in vacuo. The cruderesidue was purified by chromatography on silica gel eluting with ethylacetate, and then ethyl acetate:methanol:0.880 ammonia (94:5:1) to givethe product as a colourless oil (10 mg, 6%).

[0456] NMR (CDCl₃, selected data for the free base): 0.85 (m, 3H),1.2-1.4 (m, 6H), 1.4 (m, 2H), 1.45 (s, 3H), 1.8 (m, 2H), 2.45 (m, 2H),2.8 (m, 2H), 3.0 (m, 2H), 3.2 (m, 2H), 4.1 (m, 2H), 7.0-7.15 (m, 3H),7.2 (m, 1H).

[0457] MS (ES): M/Z (MH⁺) 381.1; C₂₀H₃₂N₂O₃S+H requires 381.2.

EXAMPLE 58

[0458]

[0459] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate (63 mg, 0.75 mmol) and1-(2-bromoethoxy)butane (38 mg, 0.20 mmol). The reaction mixture washeated for 30 h at 50° C., and then cooled to room temperature. Diethylether (5 ml) was added followed by water (7 ml), the organic extractswere separated and the aqueous layer was washed further with diethylether (2×5 ml). The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo. The residues were purified by flashchromatography on an SPE cartridge containing silica gel (5 g) elutingwith dichloromethane:ethanol:0.880 ammonia (200:8:1) to give the productas an oil (29 mg, 44%).

[0460] NMR (CDCl₃, selected data for the free base):0.95 (t, 3H), 1.35(m, 2H), 1.45 (s, 3H), 1.55 (m, 2H), 1.75 (m, 2H), 2.7 (m, 2H), 2.9-3.05(m, 7H), 3.45 (m, 2H), 3.5 (m, 2H), 7.0-7.15 (m, 3H), 7.25 (t, 1H).

[0461] MS (ES): M/Z (MH⁺) 367.1; C₁₉H₃₀N₂O₃S+H requires 367.2.

EXAMPLE 59

[0462]

[0463] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate (63 mg, 0.75 mmol) and1-(2-bromoethyl)-3-methylbenzene (A. Mitre, and S. Ghoshe, Ind. J. Chem.Sect. B, 1996, 35B, 785; 41 mg, 0.20 mmol). The reaction mixture washeated for 30 h at 50° C., and then cooled to room temperature. Diethylether (5 ml) was added followed by water (7 ml), the organic extractswere separated and the aqueous layer was washed further with diethylether (2×5 ml). The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo. The residues were purified by flashchromatography on an SPE cartridge containing silica gel (5 g) elutingwith dichloromethane:ethanol:0.880 ammonia (200:8:1) to give the productas an oil (20 mg, 29%).

[0464] NMR (CDCl₃, selected data for the free base): 1.45 (s, 3H), 1.8(m, 2H), 2.35 (s, 3H), 2.7 -2.8 (m, 4H), 2.85-3.1 (m, 7H), 7.0-7.3 (m,8H).

[0465] MS (ES): M/Z (MR⁺) 385.5; C₂₂H₂₈N₂O₂S+H requires 385.2.

EXAMPLE 60

[0466]

[0467] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate (63 mg, 0.75 mmol) and4-fluorophenoxyethyl bromide (45 mg, 0.20 mmol). The reaction mixturewas heated for 30 h at 50° C., and then cooled to room temperature.Diethyl ether (5 ml) was added followed by water (7 ml), the organicextracts were separated and the aqueous layer was washed further withdiethyl ether (2×5 ml). The combined organic extracts were dried(Na₂SO₄) and concentrated in vacuo. The residues were purified by flashchromatography 15 on an SPE cartridge containing silica gel (5 g)eluting with dichloromethane:ethanol:0.880 ammonia (200:8:1) to give theproduct as an oil (18 mg, 25%).

[0468] NMR (CDCl₃, selected data for the free base): 1.5 (s, 3H), 1.8(s, 2H), 2.9-3.15 (m, 9H), 4.05 (m, 2H), 6.8-6.9 (m, 2H), 6.95-7.15 (m,5H), 7.25 (m, 1H).

[0469] MS (ES): M/Z (MH⁺) 405.3; C₂₁H₂₅FN₂O₃S +H requires 405.2.

EXAMPLE 61

[0470]

[0471] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate (63 mg, 0.75 mmol) and 6-bromo-1-hexene(34 mg, 0.20 mmol). The reaction mixture was heated for 30 h at 50° C.,and then cooled to room temperature. Diethyl ether (5 ml) was addedfollowed by water (7 ml), the organic extracts were separated and theaqueous layer was washed further with diethyl ether (2×5 ml). Thecombined organic extracts were dried (Na₂SO₄) and concentrated in vacuo.The residues were purified by flash chromatography on an SPE cartridgecontaining silica gel (5 g) eluting with dichloromethane:ethanol:0.880ammonia (200:8:1) to give the product as an oil (29 mg, 46%).

[0472] NMR (CDCl₃, selected data for the free base): 1.4-1.45 (m, 4H),1.5 (s, 3H), 1.75 (m, 2H), 2.1 (m, 2H), 2.5 (m, 2H), 2.85 (m, 2H),2.95-3.05 (m, 5H), 4.9-5.8 (m, 1H), 7.0-7.15 (m, 3H), 7.25 (t, 1H).

[0473] MS (ES): M/Z (I) 349.5; C₁₉H₂₈N₂O₂S+H requires 349.2.

EXAMPLE 62

[0474]

[0475] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate (63 mg, 0.75 mmol) and2-[4-(bromomethyl)phenyl]acetonitrile (E. Laurent, B. Marquet and R.Tardivel, Tetrahedron, 1991, 47, 3969) (44 mg, 0.20 mmol). The reactionmixture was heated for 30 h at 50° C., and then cooled to roomtemperature. Diethyl ether (5 ml) was added followed by water (7 ml),the organic extracts were separated and the aqueous layer was washedfurther with diethyl ether (2×5 ml). The combined organic extracts weredried (Na₂SO₄) and concentrated in vacuo. The residues were purified byflash chromatography on an SPE cartridge containing silica gel (5 g)eluting with dichloromethane:ethanol:0.880 ammonia (200:8:1) to give theproduct as an oil (31 mg, 43%).

[0476] NMR (CDCl₃, selected data for the free base): 1.6 (s, 3H), 1.80(m, 2H), 2.85 (m, 2H), 3.0 -3.1 (m, 5H), 3.7 (s, 2H), 3.75 (s, 2H), 6.75(br, 1H), 7.0-7.1 (m, 3H), 7.2-7.4 (m, 5H).

[0477] MS (ES): M/Z (MH⁺) 396.0; C₂₂H₂₅N₃O₂S+H requires 396.2.

EXAMPLE 63

[0478]

[0479] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate (63 mg, 0.75 mmol) and1-(2-bromoethyl)-4-fluorobenzene (C. M. Suter, and A. W. Weston, J. Am.Chem. Soc., 1941, 6, 602; 42 mg, 0.20 mmol). The reaction mixture washeated for 30 h at 50° C., and then cooled to room temperature. Diethylether (5 ml) was added followed by water (7 ml), the organic extractswere separated and the aqueous layer was washed further with diethylether (2×5 ml). The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo. The residues were purified by flashchromatography on an SPE cartridge containing silica gel (5 g) elutingwith dichloromethane:ethanol:0.880 ammonia (200:8:1) to give the productas an oil (18 mg, 26%).

[0480] NMR (CDCl₃, selected data for the free base): 1.65 (s, 3H), 1.8(m, 2H), 2.75-2.85 (m, 4H), 2.9-3.1 (m, 7H), 6.9-7.3 (m, 8H).

[0481] MS (ES): M/Z (MH⁺) 389.0; C₂₁H₂₅FN₂O₂S+H requires 389.2.

EXAMPLE 64

[0482]

[0483] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate (63 mg, 0.75 mmol) and1-(2-bromoethyl)-2-chlorobenzene (R. A. Glennon, et al., J. Med. Chem.,1981, 24, 678; 45 mg, 0.20 mmol). The reaction mixture was heated for 30h at 50° C., and then cooled to room temperature. Diethyl ether (5 ml)was added followed by water (7 ml), the organic extracts were separatedand the aqueous layer was washed further with diethyl ether (2×5 ml).The combined organic extracts were dried (Na₂SO₄) and concentrated invacuo. The residues were purified by flash chromatography on an SPEcartridge containing silica gel (5 g) eluting withdichloromethane:ethanol:0.880 ammonia (200:8:1) to give the product asan oil (19 mg, 26%).

[0484] NMR (CDCl₃, selected data for the free base): 1.45 (s, 3H), 1.8(m, 2H), 2.75 (m, 2H), 2.85-3.1 (m, 9H), 7.0-7.4 (m, 8H).

[0485] MS ES): M/Z (MH⁺) 405.0; C₂₁H₂₅ClN₂O₂S+H requires 405.1.

EXAMPLE 65

[0486]

[0487] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate (63 mg, 0.75 mmol) and1-(2-bromoethoxy)-2-chlorobenzene (J. D. Genzer, C. P. Huttrer, and G.C. van Wessem, J. Am. Chem. Soc., 1951, 73, 3159; 49 mg, 0.20 mmol). Thereaction mixture was heated for 30 h at 50° C., and then cooled to roomtemperature. Diethyl ether (5 ml) was added followed by water (7 ml),the organic extracts were separated and the aqueous layer was washedfurther with diethyl ether (2×5 ml). The combined organic extracts weredried (Na₂SO₄) and concentrated in vacuo. The residues were purified byflash chromatography on an SPE cartridge containing silica gel (5 g)eluting with dichloromethane:ethanol:0.880 ammonia (200:8:1) to give theproduct as an oil (30 mg, 40%).

[0488] NMR (CDCl₃, selected data for the free base): 1.50 (s, 3H), 1.8(m, 2H), 3.0-3.2 (m, 9H), 4.15 (m, 2H), 6.85-6.95 (m, 2H), 7.05-7.15 (m,3H), 7.20-7.25 (m, 2H),

[0489] MS (ES): M/Z (MH³⁰ ) 421.0; C₂₁H₂₅ClN₂O₃S +H requires 421.1.

EXAMPLE 66

[0490]

[0491] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate (63 mg, 0.75 mmol) and1-(2-bromoethoxy)-2-methylbenzene (45 mg, 0.20 mmol). The reactionmixture was heated for 30 h at 50° C., and then cooled to roomtemperature. Diethyl ether (5 ml) was added followed by water (7 ml),the organic extracts were separated and the aqueous layer was washedfurther with diethyl ether (2×5 ml). The combined organic extracts weredried (Na₂SO₄) and concentrated in vacuo. The residues were purified byflash chromatography on an SPE cartridge containing silica gel (5 g)eluting with dichloromethane:ethanol:0.880 ammonia (200:8:1) to give theproduct as an oil (12 mg, 17%).

[0492] NMR (CDCl₃, selected data for the free base): 1.5 (s, 3H), 1.8(m, 2H), 2.25 (s, 3H), 2.95-3.1 (m, 5H), 3.15-3.2 (m, 4H), 4.1 (m, 2H),6.8-6.9 (m, 2H), 7.0 -7.3 (m, 6H).

[0493] MS (ES): M/Z (MH⁺) 401.0; C₂₂H₂₈N₂O₃S+H requires 401.2.

EXAMPLE 67

[0494]

[0495] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate (63 mg, 0.75 mmol) and1-(2-iodoethoxy)cyclohexane (Preparation 87, 53 mg, 0.20 mmol). Thereaction mixture was heated for 30 h at 50° C., and then cooled to roomtemperature. Diethyl ether (5 ml) was added followed by water (7 ml),the organic extracts were separated and the aqueous layer was washedfurther with diethyl ether (2×5 ml). The combined organic extracts weredried (Na₂SO₄) and concentrated in vacuo. The residues were purified byflash chromatography on an SPE cartridge containing silica gel (5 g)eluting with dichloromethane:ethanol:0.880 ammonia (200:8:1) to give theproduct as an oil (33 mg, 47%).

[0496] NMR (CDCl₃, selected data for the free base): 1.15-1.35 (m, 5H),1.45 (s, 3H),1.5 (m, 1H), 1.65-1.8 (m, 4H), 1.9 (m, 2H), 2.7 (m, 2H),2.9-3.1 (m, 7H), 3.25 (m, 2H), 7.0-7.15 (m, 3H), 7.25 (t, 1H).

[0497] MS (ES): M/Z (MH⁺) 393.1; C₂₁H₃₂N₂O₃S+H requires 393.2.

EXAMPLE 68

[0498]

[0499] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate (63 mg, 0.75 mmol) and1-[(2-iodoethoxy)methyl]benzene (Preparation 90, 54 mg, 0.20 mmol). Thereaction mixture was heated for 15 h at 50° C., and then cooled to roomtemperature. Diethyl ether (5 ml) was added followed by water (7 ml),the organic extracts were separated and the aqueous layer was washedfurther with diethyl ether (2×5 ml). The combined organic extracts weredried (Na₂SO₄) and concentrated in vacuo. The residues were purified byflash chromatography on an SPE cartridge containing silica gel (5 g)eluting with dichloromethane:ethanol:0.880 ammonia (200:8:1) to give theproduct as an oil (36 mg, 50%).

[0500] NMR (CDCl₃, selected data for the free base): 1.5 (s, 3H),1.8 (s,2H), 2.75 (m, 2H), 2.95-3.05 (m, 7H), 3.55 (m, 2H), 4.55 (s, 2H),7.0-7.1 (m, 3H), 7.2-7.4 (m, 6H).

[0501] MS (ES): M/Z (MH⁺) 401.0; C₂₂H₂₈N₂O₃S+H requires 401.2.

EXAMPLE 69

[0502]

[0503] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate (63 mg, 0.75 mmol) and1-[(E)-3-bromo-1-propenyl]cyclohexane (Preparation 88, 42 mg, 0.20mmol). The reaction mixture was heated for 15 h at 50° C., and thencooled to room temperature. Diethyl ether (5 ml) was added followed bywater (7 ml), the organic extracts were separated and the aqueous layerwas washed further with diethyl ether (2×5 ml). The combined organicextracts were dried (Na₂SO₄) and concentrated in vacuo. The residueswere purified by flash chromatography on an SPE cartridge containingsilica gel (5 g) eluting with dichloromethane:ethanol:0.880 ammonia(200:8:1) to give the product as an oil (30 mg, 43%).

[0504] NMR (CDCl₃, selected data for the free base): 1.0-1.35 (m, 6H),1.5 (s, 3H), 1.6-1.75 (m, 4H), 1.8 (m, 2H), 1.95 (m, 1H), 2.85-2.95 (m,4H), 3.0 (s, 3H), 3.1 (m, 2H), 5.4-5.6 (m, 2H), 7.0-7.15 (m, 3H), 7.15(dd, 1H).

[0505] MS (ES): M/Z (MH⁺) 389.1; C₂₂H₃₂N₂O₂S+H requires 389.2.

EXAMPLE 70

[0506]

[0507] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate (63 mg, 0.75 mmol) and4-bromo-1,1,2-trifluorobut-1-ene (39 mg, 0.20 mmol). The reactionmixture was heated for 30 h at 50° C., then further4-bromo-1,1,2-trifluorobut-1-ene (19 mg, 0.10 mmol) was added and thereaction mixture was heated for a further 13 h. After the reaction hadcooled to room temperature, diethyl ether (5 ml) was added followed bywater (7 ml), the organic extracts were separated and the aqueous layerwas washed further with diethyl ether (2×5 ml). The combined organicextracts were dried (Na₂SO₄) and concentrated in vacuo. The residueswere purified by flash chromatography on an SPE cartridge containingsilica gel (5 g) eluting with dichloromethane:ethanol:0.880 ammonia(200:8:1) to give the product as an oil (18 mg, 27%).

[0508] NMR (CDCl₃, selected data for the free base): 1.5 (s, 3H), 1.75(m, 2H), 2.45 (m, 2H), 2.7 (m, 2H), 2.85 (m, 2H), 3.0 (s, 3H), 3.1 (m,2H), 6.7 (br, 1H), 7.05-7.15 (m, 3H), 7.25 (t, 1H).

[0509] MS (ES): M/Z (MH⁺) 375.0; C₁₇H₂₁F₃N₂O₂S+H requires 375.1.

EXAMPLE 71

[0510]

[0511] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate (63 mg, 0.75 mmol) and1-(3-bromo-1-propynyl)benzene (P. Place, C. Vernière and J. Goré,Tetrahedron, 1981, 37, 1359) (40 mg, 0.20 mmol). The reaction mixturewas heated for 15 h at 50° C., and then cooled to room temperature.Diethyl ether (5 ml) was added followed by water (7 ml), the organicextracts were separated and the aqueous layer was washed further withdiethyl ether (2×5 ml). The combined organic extracts were dried(Na₂SO₄) and concentrated in vacuo. The residues were purified by flashchromatography on an SPE cartridge containing silica gel (5 g) elutingwith dichloromethane:ethanol:0.880 ammonia (200:8:1) to give the productas an oil (27 mg, 39%).

[0512] NMR (CDCl₃, selected data for the free base): 1.55 (s, 3H),1.8(m, 2H), 3.0 (s, 3H), 3.1 (m, 2H), 3.2 (m, 2H), 3.65 (s, 2H), 7.0-7.15(m, 3H), 7.2-7.35 (m, 4H), 7.4-7.45 (m, 2H).

[0513] MS (ES): M/Z (MH⁺) 381.0; C₂₂H₂₄N₂O₂S+H requires 381.2.

EXAMPLE 72

[0514]

[0515] To6-[3-(1H-benzimidazol-2-yl)phenyl]-3-hexyl-6-methyl-3-azabicyclo[3.1.0]hexan-2-one(Preparation 81, 61 mg, 1.58 mmol) in tetrahydrofuran (4 ml) stirredunder nitrogen was added lithium aluminium hydride (1M intetrahydrofuran, 0.4 ml, 0.39 mmol) dropwise over several minutes. Thereaction mixture was stirred at room temperature for 16 h, furtherlithium aluminium hydride (1M in tetrahydrofuran, 0.4 ml, 0.39 mmol) wasadded and the reaction mixture was heated under reflux for 1 h and thencooled to room temperature. The reaction mixture was quenched withaqueous sodium hydroxide solution (2M, 1.0 ml) and excess solid sodiumhydrogen carbonate was added followed by ethyl acetate (15 ml). Thereaction mixture was stirred rapidly for 30 min, filtered throughCelite® and after washing with ethyl acetate (15 ml) the combinedorganic solution was concentrated in vacuo. The crude residue waspurified by chromatography on silica gel eluting with ethyl acetate andthen ethyl acetate:methanol:0.880 ammonia (90:10:1) to give the productas a white solid (31 mg, 53%).

[0516] NMR (CDCl₃, selected data for the free base): 0.85 (m, 3H),1.2-1.4 (m, 6H), 1.4-1.5 (m, 5H), 1.6 (m, 2H), 2.4 (m, 2H), 2.75 (m,2H), 2.85 (m, 2H), 7.2-7.3 (m, 3H), 7.35 (m, 1H), 7.5 (m, 1H), 7.75-7.9(m, 2H), 8.0 (s, 1H).

[0517] MS (TSP): M/Z (MH⁺) 374.1; C₂₅H₃₁N₃+H requires 374.3.

EXAMPLE 73

[0518]

[0519] A solution of3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation12, 0.10 g, 0.37 mmol) in pyridine (8 ml) stirred under nitrogen wastreated with 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-ethanesulfonylchloride (0.50 g, 1.84 mmol). The reaction mixture was stirred at roomtemperature for 16 h and then concentrated in vacuo. The crude residuewas dissolved in dichloromethane (30 ml) and washed with saturatedaqueous sodium hydrogen carbonate solution (100 ml), the aqueous phasewas extracted with dichloromethane (2×30 ml). The combined organicextracts were dried (Na₂SO₄), filtered and concentrated in vacuo. Thecrude dark red gum was triturated with diethyl ether to give the productas a brown powder (80 mg, 42%).

[0520] NMR (CDCl₃, selected data for the free base): 0.8 (t, 3H),1.2-1.4 (m, 6H), 1.45 (m, 2H), 1.5 (s, 3H), 1.75 (m, 2H), 2.45 (m, 2H),2.8 (m, 2H), 2.95 (m, 2H), 3.5 (m, 2H), 4.05 (m, 2H), 7.0 (d, 1H), 7.1(d, 1H), 7.15-7.25 (m, 2H), 7.75 (m, 2H), 7.85 (m, 2H).

[0521] MS (ES): M/Z (MH³⁰ ) 510.1; C₂₈H₃₅N₃O₄S+H requires 510.2.

EXAMPLE 74

[0522]

[0523] A solution of2-(1,3-dioxo-1,3-2H-isoindol-2-yl-N-[3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]-1-ethanesulfonamide(Example 73, 0.70 mg, 0.14 mmol) in ethanol (3 ml) was treated withhydrazine monohydrate (6.7 μl 0.4 mmol). The reaction mixture was heatedunder reflux for 3 h, the reaction mixture was cooled and filtered, thewhite precipitate was washed with ethanol and the filtrate wasconcentrated in vacuo. The residue was purified by chromatography onsilica gel (5 g) eluting the product with a gradient of methanol:ethylacetate: 0.88 ammonia solution (10:90:1and then 20:80:1) to give theproduct as a yellowish gum (50 mg, 94%).

[0524] NMR (CDCl₃, selected data for the free base): 0.9 (m, 3H),1.2-1.4 (m, 6H), 1.45 (m, 2H 1.35 (s, 3H), 1.8 (m, 2H), 2.45 (m, 2H),2.8 (m, 2H), 3.0 (m, 2H), 3.2 (m, 2H), 3.3 (m, 2H), 7.0-7.15 (m, 3H),7.2 (m, 1 H).

[0525] MS (TSP): M/Z (MH⁺) 380.1; C₂₀H₃₃N₃O₂S+H requires 380.2.

EXAMPLE 75

[0526]

[0527] A solution of3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation12, 0.25 g, 0.93 mmol) in pyridine (10 ml) stirred under nitrogen wastreated at 0° C. with[(tert-butoxycarbonyl)amino](chloro)dioxo-λ°-sulfane (Preparation 83,0.24 g, 1.12 mmol). The reaction mixture was allowed to warm to roomtemperature and was stirred overnight before concentrating in vacuo. Thecrude gum was treated with saturated sodium hydrogen carbonate solution(100 ml) and the product was extracted with dichloromethane (3×30 ml).The combined organic solution was dried (Na₂SO₄) and concentrated invacuo to give an insoluble off white solid (0.28 g, 0.62 mmol). Thewhite solid was suspended in dichloromethane (5 ml) cooled to 0° C. andtreated dropwise with trifluoroacetic acid (1.5 ml). The reactionmixture was allowed to warm to room temperature and then stirred for 2h. The reaction mixture was poured onto 0.1M aqueous sodium carbonatesolution (50 ml) and ice (˜50 g). The mixture was stirred for 10 min andthen extracted with dichloromethane (3×20 ml). The combined organicswere dried (Na₂SO₄) and concentrated in vacuo to give a yellow solid,(130 mg, 60 %).

[0528] NMR (CDCl₃, selected data for the free base): 0.9 (m, 3H),1.25-1.4 (m, 6H), 1.4-1.5 (m, 2H), 1.5 (s, 3H), 1.75 (m, 2H), 2.45 (m,2H), 2.8 (m, 2H), 2.95 (m, 2H), 7.0-7.1 (m, 3H), 7.25 (m, 1H).

[0529] MS (ES): M/Z (MH⁺) 352.1; C₁₈H₂₉N₃O₂S+H requires 352.2.

EXAMPLE 76

[0530]

[0531]3-Hexyl-6-(3-hydroxyphenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one(Preparation 84, 0.34 g, 1.2 mmol) was dissolved in tetrahydrofuran (10ml). Lithium aluminium hydride (1M in diethyl ether, 1.5 ml, 1.5 mmol)was added under nitrogen and the reaction mixture was stirred for 1 h,before adding more lithium aluminium hydride (1M in diethyl ether, 3.0ml, 3.0 mmol) and stirring the reaction mixture for 16 h. The reactionmixture was quenched by the addition of aqueous sodium hydroxidesolution (1M, 50 ml) and the product was extracted with dichloromethane(150 ml). The organic extracts were dried (Na₂SO₄) and concentrated invacuo to give a brown waxy solid. The product was purified bychromatography on silica gel, (20 g) eluting with ethyl acetate to givethe pure product as a yellow solid (0.17 g, 51%).

[0532] NMR (CDCl₃, selected data for the free base): 0.85 (m, 3H),1.2-1.4 (m, 6H), 1.4 (s, 3H), 1.5 (m, 2H), 1.9 (m, 2H), 2.5 (m, 2H), 2.8(m, 2H), 3.2 (m, 2H), 6.6-6.7 (m, 2H), 6.8 (d, 1H), 7.1 (dd, 1H).

[0533] MS (ES): M/Z (MH⁺) 274.1; C₁₈H₂₇NO+H requires 274.2.

EXAMPLE 77

[0534]

[0535] A solution of3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation12, 0.10 g, 0.37 mmol) in pyridine (10 ml) cooled at 0° C. was treatedwith trifluoromethanesulphonyl chloride (0.14 g, 0.88 mmol) and4-dimethylaminopyridine (5 mg). The reaction mixture was stirred at roomtemperature for 3 h. The reaction mixture was concentrated in vacuo andthe residue was poured into saturated aqueous sodium hydrogen carbonatesolution (100 ml) and extracted with dichloromethane (3×50 ml). Thecombined organics were dried (Na₂SO₄) and then concentrated in vacuo.The crude residue was purified by preparative HPLC (condition 7) to givea brown solid, (17 mg, 12

[0536] NMR (CD₃OD, selected data for the free base): 0.9 (m, 3H),1.3-1.5 (m, 6H), 1.65 (m, 2H), 1.95 (s, 3H), 2.2 (m, 2H), 3.3-3.15 (m,4H), 3.8 (m, 2H), 6.85 (d, 1H), 7.0 (s, 1H), 7.05 (t, 1H).

[0537] MS (ES): M/Z (MH⁺) 405.0; C₁₉H₂₇F₃N₂O₂S+H requires 405.2.

EXAMPLE 78

[0538]

[0539] A solution of3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation12, 0.10 g, 0.37 mmol) in pyridine (8 ml) cooled at 0° C. was treatedwith 2,2,2-trifluoromethanesulphonyl chloride (0.08 g, 0.44 mmol). Thereaction mixture was allowed to warm to room temperature and thenstirred for 16 h. The reaction mixture was concentrated in vacuo and theresidue was poured into saturated aqueous sodium hydrogen carbonatesolution (100 ml) and extracted with dichloromethane (3×50 ml). Thecombined organics were dried (Na₂SO₄) and then concentrated in vacuo.The crude residue was purified by preparative HPLC (condition 7) to givea yellow solid, (15 mg, 10 %).

[0540] NMR (CD₃OD, selected data for the free base): 0.9 (m, 3H),1.2-1.4 (m, 6H), 1.45 (s, 3H), 1.5-1.6 (m, 2H), 2.0 (m, 2H), 2.65 (m,2H), 2.9 (m, 2H), 3.2 (m, 2H), 4.05 (m, 2H), 7.05-7.10 (m, 2H), 7.15 (s,1H), 7.2-7.3 (t, 1H).

[0541] MS (ES): M/Z (MH⁺) 419.0; C₂₀H₂₉F₃N₂O₂S+H requires 419.2.

EXAMPLE 79

[0542]

[0543] To a stirred solution of3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine(Preparation 8, 100 mg, 0.33 mmol) in absolute ethanol (0.5 ml) at 0°C., was added fluoroboric acid (50% in water, 0.082 ml, 0.66 mmol). Thereaction mixture was cooled to −5° C. and isoamyl nitrite (0.2 ml, 1.5mmol) was added over 10 minutes. After stirring the reaction mixture for30 minutes at −5° C., a red gum had formed. The supernatant solution wasremoved and concentrated sulphuric acid (1.5 ml) in water (4.5 ml) wasadded. The reaction mixture was stirred at 50° C. for 30 minutes andthen at room temperature for 12 h before diluting with water (50 ml) andwashing with dichloromethane (25 ml×3). The aqueous layer was basifiedto pH 10 with 0.880 ammonia solution and extracted with dichloromethane(3×25 ml). The latter organic extracts were dried (Na₂SO₄) andconcentrated in vacuo to give a yellow oil. This crude residue waspurified by chromatography on Florisil™ (5 g) eluting withdichloromethane:methanol:0.880 ammonia (98:1.5:0.5) to give a yellow oil(20 mg, 20% yield).

[0544] NMR (CDCl₃ selected data for the free base) 1.45 (s, 3H),1.75-1.85 (m, 4H), 2.50 (m, 2H), 2.65 (m, 2H), 2.85 (m, 2H), 3.10 (m,2H), 6.6-6.7 (m, 2H), 6.80 (d, 1H), 7.10-7.25 (m, 6H).

[0545] MS (APCI): M/Z (MH⁺) 307.9, C₂₁H₂₅NO+H requires 308.2

EXAMPLE 80

[0546]

[0547] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.19 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate (630 mg, 7.52 mmol) and1-(3-iodopropyl)-2-methylbenzene (EP279681 A2, 41 mg, 0.16 mmol) and thereaction mixture was heated at 50 ° C. for 20 h. After cooling, diethylether (5 ml) and water (7 ml) were added and the reaction mixture wasstirred vigorously for 5 min. The phases were separated and the aqueouslayer was further extracted with diethyl ether (2×5 ml). The combinedorganic extracts were dried (Na₂SO₄), filtered and concentrated invacuo. The residual oil was purified by flash column chromatographyusing a Sep-Pak™ cartridge packed with silica gel (5 g) eluting withdichloromethane:ethanol:0.88 ammonia solution (200:8:1) to afford thetitle compound as an oil (23 mg, 30%).

[0548] NMR (CDCl₃, selected data for the free base): 1.6 (s, 3H), 1.8(m, 2H), 2.3 (s, 3H), 2.5 (m, 2H), 2.6 (m, 2H), 2.8 (m, 2H), 3.0 (s,3H), 3.1 (m, 2H), 7.0-7.2 (m, 6H), 7.2-7.3 (m, 2H).

[0549] MS (thermospray): M/Z (MH⁺) 399.1; C₂₃H₃₀N₂O₂S+H requires 399.2.

EXAMPLE 81

[0550]

[0551] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.19 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate (630 mg, 7.52 mmol),1-(chloromethyl)4-ethylbenzene (32 mg, 0.20 mmol) and sodium iodide(catalytic) and the reaction mixture was heated at 50° C. for 20 h.After cooling, diethyl ether (5 ml) and water (7 ml) were added and thereaction mixture was stirred vigorously for 5 min. The phases wereseparated and the aqueous layer was further extracted with diethyl ether(2×5 ml). The combined organic extracts were dried (Na₂SO₄), filteredand concentrated in vacuo. The residual oil was purified by flash columnchromatography using a Sep-Pak™ cartridge packed with silica gel (5 g)eluting with dichloromethane:ethanol:0.88 ammonia solution (200:8:1) toafford the title compound as an oil (30 mg, 41%).

[0552] NMR (CDCl₃, selected data for the free base):1.2 (t, 3H), 1.6 (s,3H), 2.6 (q, 2H), 3.0 (s, 3H), 3.1 (m, 2H), 3.6 (m, 2H), 7.0-7.3 (m,8H).

[0553] MS (thermospray): M/Z (MH⁺) 384.8; C₂₂H₂₈N₂O₂S+H requires 385.2.

EXAMPLE 82

[0554]

[0555] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.19 mmol) dissolved in N,N-dimethylformamide (2ml) was added sodium hydrogen carbonate (630 mg, 7.52 mmol) and1-bromo-2-hexyne (H. A. J. Charles, and R. J. Batten, J. Chem. Soc.,Perkin Trans 1, 1987, 1999, 33 mg, 0.2 mmol) and the reaction mixturewas heated at 50° C. for 20 h. After cooling diethyl ether (5 ml) andwater (7 ml) were added and the reaction mixture was stirred vigorouslyfor 5 min. The phases were separated and the aqueous layer was furtherextracted with diethyl ether (2×5 ml). The combined organic extractswere dried (Na₂SO₄), filtered and concentrated in vacuo. The residualoil was purified by flash column chromatography using a Sep-Pak™cartridge packed with silica gel (5 g) eluting withdichloromethane:ethanol:0.88 ammonia solution (200:8:1) to afford thetitle compound as an oil (33 mg, 50%).

[0556] NMR (CDCl₃, selected data for the free base): 1.0 (t, 3H),1.45-1.6 (m, 5H), 1.8 (m, 2H), 2.2 (t, 2H), 2.95-3.1 (m, 7H), 3.4 (m,2H), 7.0-7.1 (m, 3H), 7.25 (m, 1H).

[0557] MS (thermospray): M/Z (MH⁺) 347.0; C₁₉H₂₆N₂O₂S+H requires 347.2.

EXAMPLE 83

[0558]

[0559] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.19 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate (630 mg, 7.52 mmol),2-chloro-N-cyclohexylacetamide (36 mg, 0.2mmol) and sodium iodide(catalytic) and the reaction was heated at 50° C. for 20 h. Aftercooling diethyl ether (5 ml) and water (7 ml) were added and thereaction mixture was stirred vigorously for 5 min. The phases wereseparated and the aqueous layer was further extracted with diethyl ether(2×5 ml). The combined organic extracts were dried (Na₂SO₄), filteredand concentrated in vacuo. The residual oil was purified by flash columnchromatography using a Sep-Pak™ cartridge residual oil was purified byflash column chromatography using a Sep-Pak™ cartridge (200:8:1) toafford the title compound as an oil (22 mg, 28%).

[0560] NMR (CDCl₃, selected data for the free base):1.1-1.3 (m, 3H),1.3-2.0 (m, 12H), 2.9-3.2 (m, 10H), 3.8 (m, 2H), 6.6 (br, 1H), 6.8 (m,1H), 7.0-7.3 (m, 4H).

[0561] MS (electrospray): M/Z (MH⁺) 406.1; C₂₁H₃₁N₃O₃S+H requires 406.2.

EXAMPLE 84

[0562]

[0563] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.19 mmol) in dimethoxyethyl ether (2 ml) wasadded sodium hydrogen carbonate (630 mg, 7.52 mmol), and3-cyclohexyl-3-oxopropyl-4-bromobenzenesulfonate (Preparation 91, 75 mg,0.2 mmol) and the reaction mixture was heated at 50° C. for 20 h. Aftercooling, diethyl ether (5 ml) and water (7 ml) were added and thereaction mixture was stirred vigorously for 5 min. The phases wereseparated and the aqueous layer was further extracted with diethyl ether(2×5 ml). The combined organic extracts were dried (Na₂SO₄), filteredand concentrated in vacuo. The residual oil was purified by flash columnchromatography using a Sep-Pak™ cartridge packed with silica gel (5 g)eluting with dichloromethane:ethanol:0.88 ammonia solution (200:8:1) toafford the title compound as an oil (42 mg, 52%).

[0564] NMR (CDCl₃, selected data for the free base): 1.1-1.3 (m, 6H),1.6-1.9 (m, 10H), 2.3 (m, 1H), 2.6 (t, 2H), 2.7-2.85 (m, 4H), 3.0-3.1(m, 5H), 7.0-7.15 (m, 3H), 7.2 (m, 1H).

[0565] MS (electrospray): M/Z (MH⁺) 405.1; C₂₂H₃₂N₂O₃S +H requires405.2.

EXAMPLE 85

[0566]

[0567] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 57 mg, 0.19 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate (630 mg, 7.52 mmol) and1-adamantyl-2-iodoethane (Preparation 93, 58 mg, 0.2 mmol) and thereaction was heated at 50° C. for 20 h. After cooling diethyl ether (5ml) and water (7 ml) were added and the reaction mixture was stirredvigorously for 5 min. The phases were separated and the aqueous layerwas further extracted with diethyl ether (2×5 ml). The combined organicextracts were dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidual oil was purified by flash column chromatography using aSep-Pak™ cartridge packed with silica gel (5 g) eluting withdichloromethane:ethanol:0.88 ammonia solution (200:8:1) to afford thetitle compound as an oil (32 mg, 39%).

[0568] NMR (CDCl₃, selected data for the free base): 1.2 (m, 3H),1.5-1.8 (m, 13H), 1.9 (m, 2H), 2.8-2.9 (m, 2H), 3.0 (s, 3H), 7.0-7.3 (m,4H).

[0569] MS (electrospray): M/Z (MH⁺) 429.2; C₂₅H₃₆N₂O₂S+H requires 429.3.

EXAMPLE 86

[0570]

[0571] A solution of3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation12, 2.7 g, 8.8 mmol) in hydrochloric acid (2 M, 20 ml) was cooled in anice bath and treated dropwise with a solution of sodium nitrite (1.3 g,19 mmol) in water (20 ml). The reaction mixture was stirred for 30minutes and then a solution of potassium iodide (3.1 g, 19 mmol) inwater (20 ml) was added slowly. The reaction mixture was allowed to warmto room temperature over 3 h and then heated at 90° C. for 5 minutes,before cooling and slowly pouring onto aqueous saturated sodium hydrogencarbonate (100 ml). The reaction mixture was then extracted with ethylacetate (4×75 ml) and the dark organic extracts were washed with aqueoussodium thiosulphate (10% w/w, 100 ml). The combined organic extractswere dried (MgSO₄) and then concentrated in vacuo to give a black oil(1.2 g). The crude residue was purified by chromatography on silica gel(100 g) eluting with hexane:ethyl acetate (70:30 and then 30:70) to givea black oil (160 mg, 12%).

[0572] NMR (CDCl₃, selected data for the free base): 1.55 (s, 3H),1.70-1.85 (m, 4H), 2.50 (t, 2H), 2.65 (t, 2H), 2.80 (m, 2H), 3.05 (m,2H), 7.00 (m, 1H), 7.05-7.20 (m, 6H), 7.50 (d, 1H), 7.65 (s,1H).

[0573] MS (APCI): M/Z (MH⁺) 418.0: C₂₁H₂₄ ¹²⁹IN+H requires 418.1

EXAMPLE 87

[0574]

[0575] To a degassed solution of6-(3-iodophenyl)-6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hexane(Example 86, 490 mg, 1.18 mmol) in toluene (20 ml) was addedtetrakistriphenylphosphine palladium (0) (0.68 g, 0.60 mmol) and afinely crushed mixture of potassium cyanide (320 mg, 5.0 mmol) andneutral activated alumina (640 mg) under nitrogen. The reaction mixturewas heated to 80° C. for 3 h, and then at reflux for 30 minutes beforecooling to room temperature and concentrating in vacuo. The mixture wasabsorbed onto silica gel (7 g) and then purified by chromatography onsilica gel (100 g) eluting with hexane:ethyl acetate (95:5 and then50:50) to give a red solid (165 mg, 44%).

[0576] NMR (CDCl₃, selected data for the free base): 1.60 (s, 3H),1.70-1.85 (m, 4H), 2.50 (t, 2H), 2.65 (t, 2H), 2.80 (m, 2H), 3.10 (m,2H), 7.10-7.60 (m, 9H).

[0577] MS (APCI): M/Z (MH⁺) 317.0: C₂₂H₂₄N₂+H requires 317.2

EXAMPLE 88

[0578]

[0579] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 200 mg, 0.89 mmol) in N,N-dimethylformamide (8 ml) wasadded sodium hydrogen carbonate (3 g, 36 mmol) and 3-bromo-1-propanol(0.08 ml, 0.89 mmol), the reaction mixture was heated at 50° C. for 20h. After cooling, diethyl ether (15 ml) and water (15 ml) were added andthe reaction mixture was stirred vigorously for 5 min. The phases wereseparated and the aqueous layer was further extracted with diethyl ether(2×15 ml). The combined organic extracts were dried (Na₂SO₄), filteredand concentrated in vacuo. The residual oil was purified by flash columnchromatography using a Sep-Pak™ cartridge packed with silica gel (10 g)eluting with dichloromethane:ethanol:0.88 ammonia solution (200:8:1) toafford the title compound as an oil (42 mg, 15%).

[0580] NMR (CDCl₃, selected data for the free base): 1.4 (s, 3H), 1.7(m, 2H), 2.0 (m, 2H), 2.8 (m, 2H), 3.0-3.2 (m, 5H), 3.8 (m, 2H), 7.8-7.1(m, 3H), 7.3 (m, 1H)

[0581] MS (thermospray): M/Z (MH⁺) 325.1; C₁₆H₂₄N₂O₃S+H requires 325.2.

EXAMPLE 89

[0582]

[0583] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 200 mg, 0.89 mmol) in N,N-dimethylformamide (8 ml) wasadded sodium hydrogen carbonate (3 g, 36 mmol) and1-[(E)-3-bromo-1-propenyl]benzene (0.13 ml, 0.89 mmol) and the reactionmixture was heated at 50° C. for 20 h. After cooling, diethyl ether (15ml) and water (15 ml) were added and the reaction mixture was stirredvigorously for 5 min. The phases were separated and the aqueous layerwas further extracted with diethyl ether (2×15 ml). The combined organicextracts were dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidual oil was purified by flash column chromatography using aSep-Pak™ cartridge packed with silica gel (10 g) eluting withdichloromethane:ethanol:0.88 ammonia solution (200:8:1) to afford thetitle compound as an oil (40 mg, 12%).

[0584] NMR (CDC₃, selected data for the free base): 1.6 (s, 3H), 1.8 (m,2H), 2.9-3.1 (m, 9H), 3.3 (m, 2H), 6.25 (m, 1H), 6.5 (d, 1H), 7.0-7.1(m, 7H)

[0585] MS (thermospray): M/Z (MH⁺) 383.3; C₂₂H₂₆N₂O₂S+H requires 383.2.

EXAMPLE 90

[0586]

[0587] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 200 mg, 0.66 mmol) in N,N-dimethylformamide (8 ml) wasadded sodium hydrogen carbonate (3 g, 36 mmol) and(S)-3-cyclohexyl-3-hydroxypropyl 4-bromobenzenesulfonate (J. A. Werneret al, J. Org. Chem., 1996, 61, 587) (0.08 ml, 0.89 mmol) and thereaction mixture was heated at 50° C. for 20 h. After cooling, diethylether (15 ml) and water (15 ml) were added and the reaction mixture wasstirred vigorously for 5 min. The phases were separated and the aqueouslayer was further extracted with diethyl ether (2×15 ml). The combinedorganic extracts were dried (Na₂SO₄), filtered and concentrated invacuo. The residual oil was purified by flash column chromatographyusing a Sep-Pak™ cartridge packed with silica gel (10 g) eluting withdichloromethane:ethanol:0.88 ammonia solution (200:8:1) to afford thetitle compound as an oil (90 mg, 25%).

[0588] NMR (CDCl₃, selected data for the free base): 0.9-1.1 (m, 2H),1.2-1.4 (m, 6H), 1.5 (m, 2H), 1.6-1.8 (m, 6H), 1.9-2.0 (m, 1H),2.65-2.95 (m, 4H), 3.0 (s, 2H), 3,5 (q, 1H), 3.7 (q, 1H), 7.0 (m, 3H),7.3 (m, 1H)

[0589] MS (thermospray): M/Z (MH⁺) 407.0 C₂₂H₃₄N₂O₃S+H requires 407.2.

EXAMPLE 91

[0590]

[0591] To a solution of[6-(3-aminophenyl)-3-hexyl-3-azabicyclo[3.1.0]hex-6-yl]methanol(Preparation 94, 15 mg, 0.052 mmol) in anhydrous pyridine (0.2 ml) at 0°C. under nitrogen was added methanesulfonyl chloride (4.3 μl, 6.3 mg, 55μmol) freshly distilled over phosphorous pentoxide. The reaction wasstirred for 2 h and gradually allowed to warm to room temperature. Themixture was poured into aqueous sodium hydroxide (1N, 5 ml) and dilutedwith water (20 ml). The aqueous phase was extracted with ethyl acetate(2×25 ml) and the combined organic layers were washed with brine (25ml). The combined organic extracts were dried (MgSO₄) and thenconcentrated in vacuo. The crude product was chromatographed on Merck230-400 mesh silica gel (5 g) eluting with ethyl acetate:2M ammonia inethanol (98:2) to give the desired compound as a pale yellow oil (5 mg,26%).

[0592] NMR (CDCl₃, selected data for the free base): 0.90 (m, 3H),1.20-1.35 (m, 6H), 1.45 (m, 2H), 1.85 (br s, 2H), 2.50 (t, 2H), 2.65 (brd, 2H), 3.00 (s, 3H), 3.40 (d, 2H), 7.00-7.20 (m, 4H).

[0593] MS (Thermospray): M/Z (MH⁺) 366.9; C₁₉H₃₀N₂O₃S+H requires 367.2

EXAMPLE 92

[0594]

[0595] To a solution of3-[3-hexyl-6-(methoxymethyl)-3-azabicyclo[3.1.0]hex-6-yl]aniline(Preparation 98, 11 mg, 0.036 mmol) in anhydrous pyridine (0.3 ml) at 0°C. under nitrogen was added methanesulfonyl chloride (3.4 μl, 5 mg, 43μmol) freshly distilled from phosphorous pentoxide. The reaction wasstirred for 3 h and quenched by the addition of water (5 ml) andsaturated sodium carbonate solution (25 ml). The aqueous layer wasextracted with ethyl acetate (2×25 ml) and the organic extracts werewashed with brine (25 ml). The organic layers were dried (MgSO₄) andthen concentrated in vacuo. The crude product was chromatographed onMerck 230-400 mesh silica gel (5 g) eluting with ethyl acetate: 2Mammonia in ethanol (99:1) to give the desired product as a pale yellowoil (11 mg, 79%).

[0596] NMR (CDCl₃, selected data for the free base): 0.90 (m, 3H),1.15-1.45 (m, 811), 1.80 (br s, 2H), 2.40 (t, 2H), 2.70 (br d, 2H), 3.00(s, 3H), 3.20 (d, 2H), 3.30 (s, 3H), 4.10 (s, 2H), 7.00 (d, 1H),7.10-7.20 (m, 2H), 7.25 (m, 1H).

[0597] MS (Thermospray): M/Z (MH⁺) 380.6; C₂₀H₃₂N₂O₃S requires 380.6

EXAMPLE 93

[0598]

[0599] 3-[3-Hexyl-6-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hex-6-ylaniline (Preparation 101, 143 mg, 0.42 mmol) was dissolved in anhydrousdichloromethane (3 ml) in a dry, nitrogen-flushed flask and cooled to−12° C. in an ice/methanol bath. Pyridine (54 μl, 0.67 mmol) was addeddropwise followed by methanesulfonyl chloride (39 μl, 0.50 mmol). Themixture was allowed to slowly warm to room temperature, whereupon itscolour changed from yellow to bright amber. After 3 h, the mixture wastreated with water (20 ml) and extracted with dichloromethane (3×20 ml).The combined organic extracts were washed with brine (20 ml), dried(MgSO₄), filtered and the solvent removed in vacuo. The crude productwas purified by chromatography on silica gel (5 g), eluting withhexane:ether (2:1) to give the product as an amber gum (71 mg, 40%).

[0600] NMR (CDCl₃, selected data for the free base): 0.85-0.95 (m, 3H),1.20-1.35 (m, 6H), 1.35-1.45 (m, 2H), 1.85 (m, 2H), 2.40 (t, 2H), 2.60(d, 2H), 2.95 (s, 3H), 3.15 (q 2H), 2.25 (d, 2H), 7.05, (d, 1H), 7.10(d, 1H), 7.20 (s, 1H), 7.25 (s, 1H).

[0601] MS (Thermospray): (MH⁺) 419.4, C₂₀H₂₉F₃N₂O₂S+H requires 419.5.

EXAMPLE 94

[0602]

[0603] To a solution of6-(3-aminophenyl)-3-hexyl-3-azabicyclo[3.1.0]hexane-6-carbonitrile(Preparation 105, 1.7 mg, 6.0 μmol) in anhydrous pyridine (0.2 ml) at 0°C. under nitrogen was added methanesulfonyl chloride (0.5 μl, 0.8 mg,6.6 μmol) which had been freshly distilled over phosphorous pentoxide.The reaction was stirred for 2 h and gradually allowed to warm to roomtemperature. The mixture was poured into saturated sodium carbonatesolution (5 ml) and diluted with water (20 ml). The aqueous phase wasextracted with ethyl acetate (2×25 ml) and the organic extracts werewashed with brine (25 ml). The combined organic extracts were dried(MgSO₄) and then concentrated in vacuo. The crude product waschromatographed on Merck 230-400 mesh silica gel (5 g) eluting withethyl acetate:hexane:2M ammonia in ethanol (50:49:1) to give the desiredcompound as a pale yellow oil (2 mg, 92%).

[0604] NMR (CDCl₃, selected data for the free base): 0.90 (m, 3H),1.20-1.35 (m, 6H), 1.50 (m, 2H), 2.20 (m, 2H), 2.50 (m, 2H), 2.85 (m,2H), 3.00 (s, 3H), 3.30 (m, 2H), 7.10-7.30 (m, 4H).

[0605] MS (Thermospray): M/Z (MH⁺) 362.1; C₁₉H₂₇N₃O₂S+H requires 362.2

EXAMPLE 95

[0606]

[0607] A solution ofN-{[6-(3-aminophenyl)-3-hexyl-3-azabicyclo[3.1.0]hex-6-yl]methyl}acetamide(Preparation 108, 67 mg, 0.203 mmol) in dry pyridine (0.5 ml) wasstirred under nitrogen and cooled in an ice bath. Methanesulfonylchloride (0.02 ml, 0.258 mmol) was added dropwise and the reactionmixture was allowed to warm to room temperature with stirring over 16 h.The mixture was then diluted with dichloromethane (5 ml) and washed withsaturated aqueous sodium hydrogen carbonate solution (5 ml). The aqueousphase was washed with dichloromethane (2×5 ml) and the combined organicphases were dried (Na₂SO₄) and concentrated in vacuo to give an orangeresidue (80 mg). Purification was effected by column chromatography onsilica gel (4 g) eluting with dichloromethane:ethanol:0.88 ammonia(200:8:1 and then 150:8:1) to give the title compound as a cream foam(65 mg, 78%).

[0608] NMR (CDCl₃): 0.90 (m, 3H), 1.20-1.35 (m, 6H), 1.45 (m, 2H), 1.85(m, 2H), 1.90 (s, 3H), 2.45 (m, 2H), 2.75 (m, 2H), 3.00 (s, 3H), 3.20(m, 2H), 4.00 (m, 2H), 5.65 (m, 1H), 7.00-7.10 (m, 2H), 7.20-7.30 (m,2H).

[0609] MS (thermospray): M/Z (MH⁺) 408.4; C₂₁H₃₃N₃O₃S+H requires 408.2.

EXAMPLE 96

[0610]

[0611] A solution of[6-(3-aminophenyl)-3-hexyl-3-azabicyclo[3.1.0]hex-6-yl]methanol(Preparation 94, 0.03 g, 0.09 mmol) in tetrahydrofuran (2 ml), stirredunder nitrogen and cooled to 0° C., was treated with triethylamine (0.03ml, 0.19 mmol) and acetyl chloride (0.01 ml, 0.17 mmol). The reactionmixture was stirred at room temperature for 3 h, saturated aqueoussodium hydrogen carbonate (50 ml) was added and the product wasextracted with ethyl acetate (25 ml×3). The combined organic extractswere dried (Na₂SO₄) and then concentrated in vacuo. The crude residuewas purified on a Sep-Pak™ cartridge packed with silica gel (5 g) togive the product as a clear glass, (11 mg, 34%).

[0612] NMR (CDCl₃, selected data for the free base): 0.90 (m, 3H),1.20-1.35 (m, 6H), 1.40 (m, 2H), 1.85 (s, 2H), 1.95 (s, 3H), 2.40 (t,2H), 2.65 (m, 2H), 3.20 (m, 2H), 2.80 (s, 2H), 7.05 (m, 1H), 7.15-7.30(m, 2H), 7.45 (s, 1H).

[0613] MS (ES): M/Z (MH³⁰ ) 373.3; C₂₂H₃₂N₂O₃+H requires 373.2.

EXAMPLE 97

[0614]

[0615] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 50 mg, 0.165 mmol) in N,N-dimethylformamide (2 ml) wasadded sodium hydrogen carbonate (35 mg, 0.413 mmol) and3-(2-bromoethyl)indole (37 mg, 0.165 mmol). The reaction mixture washeated at 55° C. for 48 h, cooled to room temperature and concentratedin vacuo. Water (10 ml) was added and the product was extracted withethyl acetate (3×10 ml). The combined organic extracts were dried(Na₂SO₄), filtered and concentrated in vacuo to give a brown oil. Thecrude product was purified by chromatography using a Biotage Flash 12™cartridge packed with silica gel (8 g), eluting with hexane:ethylacetate (100:0 and then 0:100). The title compound was obtained as aglass (22 mg, 33%).

[0616] NMR (CD₃OD, selected data for the hydrochloride salt): 1.5 (s,3H), 1.8 (m, 2H), 2.8-3.15 (m, 11H), 7.0-7.3 (m, 7H), 7.4 (d, 1H), 7.8(d, 1H), 8.0 (br, 1H).

[0617] MS (thermospray): M/Z (MH⁺) 410.2; C₂₃H₂₇N₃O₂S+H requires 410.2.

EXAMPLE 98

[0618]

[0619] A solution ofN-[3-(6-methyl-3-{2-[4-(trifluoromethyl)phenyl]acetyl}-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 114, 65 mg, 0.144 mmol) in anhydrous tetrahydrofuran (1.0ml) was stirred under a nitrogen atmosphere and cooled to 0° C. Thesolution was treated dropwise with lithium aluminium hydride (1.0Msolution in tetrahydrofuran, 0.28 ml, 0.28 mmol) and then stirred atroom temperature for 18 h. The rapidly stirred reaction mixture wastreated with water (0.28 ml), sodium hydrogen carbonate (200 mg) andethyl acetate (15 ml). After 30 min the reaction mixture was filteredand concentrated in vacuo to afford a colourless oil. The residue waspartially purified by chromatography using a Sep-Pak™ cartridge packedwith silica gel (10 g) eluting with dichloromethane:ethanol:0.88 ammonia(300:8:1) to afford an off-white solid. This was further purified bypreparative HPLC (condition 8) to give the title compound as anoff-white solid (22 mg, 35%. m.p. 159-161° C.

[0620] NMR (CD₃OD, selected data for the free base): 1.40 (s, 3H), 1.80(m, 2H), 2.75-2.85 (m, 4H), 2.90 (s, 3H), 2.90-3.00 (m, 4H), 7.02 (m,2H), 7.10 (br. s, 1H), 7.20 (d, 2H), 7.75 (d, 2H).

[0621] MS (thermospray): M/Z (MH⁺) 439.3; C₂₂H₂₅F₃N₂O₂S+H requires439.2.

EXAMPLE 99

[0622]

[0623] To a solution ofN-{3-[3-(2,3-dihydro-1H-inden-2-ylcarbonyl)-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide(Preparation 115, 94 mg, 0.23 mmol) in anhydrous tetrahydrofuran (2 ml)under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.40 ml, 0.40 mmol)and the mixture was stirred at room temperature for 3 h. The rapidlystirred reaction mixture was treated sequentially with water (0.40 ml),sodium hydrogen carbonate (400 mg) and ethyl acetate (15 ml). After 30min the reaction mixture was filtered and concentrated in vacuo toafford a colourless oil. This was purified by preparative HPLC(condition 8) to give a light brown oil which was partitioned betweendichloromethane (10 ml) and aqueous potassium carbonate solution (4%w:v, 5 ml). The layers were separated and the organic layer was washedwith water (3 ml) and saturated brine (2 ml), dried (Na₂SO₄), filteredand concentrated in vacuo to afford the title compound as a colourlessoil (62 mg, 68%). The free base (55 mg, 0.14 mmol) was dissolved inanhydrous diethyl ether (5 ml) and dichloromethane (1 ml) and thesolution was treated with hydrogen chloride (1.0M solution in diethylether, 0.153 ml). The heterogeneous suspension was concentrated in vacuoto afford the hydrochloride salt of the title compound as a white solid(50 mg, 83%).

[0624] NMR (CD₃OD, selected data for the hydrochloride salt): 1.50 (s,3H), 2.40 (m, 2H), 2.70-2.90 (m, 3H), 2.95 (s, 3H), 3.05-3.30 (m, 4H),3.40-3.60 (m, 3H), 4.18 (br. d, 1H), 7.00-7.37 (m, 8H).

[0625] MS (thermospray): M/Z (MH⁺) 397.5; C₂₃H₂₈N₂O₂S+H requires 397.2.

EXAMPLE 100

[0626]

[0627] To a solution ofN-(3-{3-[2-(1-benzothiophen-3-yl)]-6-methyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 116, 87 mg, 0.2 mmol) in anhydrous tetrahydrofuran (2 ml)under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.40 ml, 0.40 mmol)and the mixture was stirred at room temperature for 3 h. The rapidlystirred reaction mixture was treated sequentially with water (0.40 ml),sodium hydrogen carbonate (400 mg) and ethyl acetate (15 ml). After 30min the reaction mixture was filtered and concentrated in vacuo toafford a colourless oil. This was purified by preparative HPLC(condition 8) to give a light brown oil which was partitioned betweendichloromethane (10 ml) and aqueous potassium carbonate solution (4%w:v, 5 ml). The layers were separated and the organic layer was washedwith water (3 ml), dried (Na₂SO4), filtered and concentrated in vacuo toafford the title compound as a colourless oil (45 mg, 53%).

[0628] NMR (CDCl₃, selected data ): 1.50 (s, 3H), 1.85 (br., 2H),2.90-3.20 (m, 11H), 7.00-7.15 (m, 3H), 7.15-7.30 (m, 2H), 7.30-7.45 (m,2H), 7.80 (d, lH), 7.85 (d, 1H).

[0629] MS (thermospray): M/Z (MH⁺) 427.3; C₂₃H₂₆N₂O₂S₂+H requires 427.2.

EXAMPLE 101

[0630]

[0631] To a solution ofN-(3-{6-methyl-3-[2-(1-methyl-1H-indol-3-yl)acetyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 117, 55 mg, 0.126 mmol) in anhydrous tetrahydrofuran (1 ml)under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.26 ml, 0.26 mmol)and the reaction mixture was stirred at room temperature for 3 h. Therapidly stirred reaction mixture was treated sequentially with water(0.26 ml), sodium hydrogen carbonate (250 mg) and ethyl acetate (10 ml).After 30 min, the reaction mixture was filtered and concentrated invacuo to afford a colourless oil. This was purified by preparative HPLC(condition 8) to give a pale yellow oil which was partitioned betweendichloromethane (10 ml) and aqueous potassium carbonate solution (4%w:v, 5 ml). The layers were separated and the organic layer was washedwith water (3 ml), dried (Na₂SO₄), filtered and concentrated in vacuo toafford the title compound as a colourless oil (28 mg, 52%).

[0632] NMR (CDCl₃, selected data for the free base): 1.50 (br. s, 3H),1.85 (m, 2H), 2.80-3.20 (m, 11H), 3.75 (s, 3H), 6.90 (s, 1H), 7.00-7.18(m, 4H), 7.20-7.35 (m, 3H), 7.66 (d, 1H).

[0633] MS (thermospray): M/Z MH⁺) 424.1; C₂₄H₂₉N₃O₂S+H requires 424.2.

EXAMPLE 102

[0634]

[0635] To a solution ofN-(3-{3-[3-(4-fluorophenyl)propanoyl]-6-methyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 118, 86 mg, 0.21 mmol) in anhydrous tetrahydrofuran (2 ml)under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.42 ml, 0.42 mmol)and the mixture was stirred at room temperature for 3 h. The rapidlystirred reaction mixture was treated sequentially with water (0.42 ml),sodium hydrogen carbonate (400 mg) and ethyl acetate (10 ml). After 30min the reaction mixture was filtered and concentrated in vacuo toafford a colourless oil. The oil was purified by preparative HPLC(condition 8) to give a pale yellow oil which was partitioned betweendichloromethane (10 ml) and aqueous potassium carbonate solution (4%w:v, 5 ml). The layers were separated and the organic layer was washedwith water (3 ml), dried (Na₂SO₄), filtered and concentrated in vacuo toafford the title compound as a colourless oil (52 mg, 62%). The freebase (45 mg, 0.112 mmol) was dissolved in anhydrous diethyl ether (5 ml)and dichloromethane (1 ml) and the solution was treated with hydrogenchloride (1.0M solution in diethyl ether, 0.123 ml). The heterogeneoussuspension was concentrated in vacuo to afford the hydrochloride salt ofthe title compound as a white solid (46 mg, 94%).

[0636] NMR (CD₃OD, selected data for the hydrochloride): 1.45 (s, 3H),2.00 (m, 2H), 2.35 (m, 2H), 2.70 (m, 2H), 2.95 (s, 3H), 3.00-3.40 (m,6H), 7.00-7.15 (m, 4H), 7.2-7.35 (m, 4H).

[0637] MS (thermospray): M/Z (MH⁺) 403.3; C₂₂H₂₇FN₂O₂S+H requires 403.2.

EXAMPLE 103

[0638]

[0639] To a solution ofN-(3-{3-[3-(3,4-dichlorophenyl)propanoyl]-6-methyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 119, 30 mg, 0.06 mmol) in anhydrous tetrahydrofuran (1 ml)under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.12 ml, 0.12 mmol)and the mixture was stirred at room temperature for 3 h. The rapidlystirred reaction mixture was treated sequentially with water (0.12 ml),sodium hydrogen carbonate (200 mg) and ethyl acetate (10 ml). After 30min the reaction mixture was filtered and concentrated in vacuo to givea colourless oil. This was purified by preparative HPLC (condition 8) toafford the title compound as a pale yellow oil (5.2 mg, 19%).

[0640] MS (thermospray): M/Z (MH⁺) 453.1; C₂₂H₂₆Cl₂N₂O₂S+H requires453.1.

EXAMPLE 104

[0641]

[0642] To a solution ofN-(3-{3-[3-(1,3-benzodioxol-5-yl)propanoyl]-6-methyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 120, 96 mg, 0.22 mmol) in anhydrous tetrahydrofuran (2 ml)under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.44 ml, 0.44 mmol)and the mixture was stirred at room temperature for 3 h. The rapidlystirred reaction mixture was treated sequentially with water (0.44 ml),sodium hydrogen carbonate (400 mg) and ethyl acetate (10 ml). After 30min the reaction mixture was filtered and concentrated in vacuo toafford a colourless oil. This was purified by preparative HPLC(condition 8) to give a pale yellow oil which was partitioned betweendichloromethane (10 ml) and aqueous potassium carbonate solution (4%w:v, 5 ml). The layers were separated and the organic layer was washedwith water (3 ml), dried (Na₂SO₄), filtered and concentrated in vacuo toafford the title compound as a colourless oil (32 mg, 34%). The freebase (23 mg, 0.054 mmol) was dissolved in anhydrous diethyl ether (5 ml)and dichloromethane (1 ml) and the solution was treated with hydrogenchloride (1.0M solution in diethyl ether, 0.06 ml). The heterogeneoussuspension was concentrated in vacuo to afford the hydrochloride salt ofthe title compound as a white solid (20 mg, 80%).

[0643] NMR (CD₃OD, selected data for the hydrochloride salt): 1.45 (s,3H), 1.95 (br., 2H), 2.35 (m, 2H), 2.65 (m, 2H), 2.95 (s, 3H), 3.00-3.40(m, 6H), 5.90 (m, 2H), 6.65-6.80 (m, 3H), 7.05-7.35 (m, 4H).

[0644] MS (thermospray): M/Z (MH⁺) 429.0; C₂₃H₂₈N₂O₄S+H requires 429.2.

EXAMPLE 105

[0645]

[0646] To a solution ofN-(3-{3-[2-(5-chloro-3-thienyl)acetyl]-6-methyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 121, 45 mg, 0.11 mmol) in anhydrous tetrahydrofuran (1 ml)under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.22 ml, 0.22 mmol)and the mixture was stirred at room temperature for 3 h. The rapidlystirred reaction mixture was treated sequentially with water (0.22 ml),sodium hydrogen carbonate (200 mg) and ethyl acetate (10 ml). After 30min the reaction mixture was filtered and concentrated in vacuo toafford a pale yellow oil. This was purified by preparative BPLC(condition 8) to give a very pale yellow oil which was partitionedbetween dichloromethane (10 ml) and aqueous potassium carbonate solution(4% w:v, 5 ml). The layers were separated and the organic layer waswashed with water (3 ml), dried (Na₂SO₄), filtered and concentrated invacuo to afford the title compound as a colourless oil (14 mg, 33%).

[0647] NMR (CDCl₃, selected data for the free base): 1.25 (s, 3H), 1.80(m, 2H), 2.75-3.10 (m, 11H), 6.60 (m, 1H), 6.70 (m, 1H), 7.00-7.15 (m,3H), 7.25 (m, 1H).

[0648] MS (electrospray): M/Z (MH⁺) 411.1; C₁₉H₂₃ClN₂O₂S₂+H requires411.1.

EXAMPLE 106

[0649]

[0650] To a solution ofN-{3-[6-methyl-3-(3-methyl-3-phenylbutanoyl)-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide(Preparation 122, 59 mg, 0.138 mmol) in anhydrous tetrahydrofuran (1 ml)under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.28 ml, 0.28 mmol)and the mixture was stirred at room temperature for 3 h. The rapidlystirred reaction mixture was treated sequentially with water (0.28 ml),sodium hydrogen carbonate (200 mg) and ethyl acetate (10 ml). After 30min the reaction mixture was filtered and concentrated in vacuo toafford a pale yellow oil. This was purified by preparative BPLC(condition 8) to give a light brown oil which was partitioned betweendichloromethane (15 ml) and aqueous potassium carbonate solution (7%w:v, 5 ml). The layers were separated and the organic layer was washedwith water (5 ml), dried (MgSO₄), filtered and concentrated in vacuo toafford the title compound as a colourless oil (38 mg, 66%).

[0651] NMR (CDCl₃, selected data for the free base): 1.30 (s, 6H), 1.40(s, 3H), 1.70-1.90 (m, 4H), 2.35 (m, 2H), 2.80-3.00 (m, 4H), 3.00 (s,3H), 7.00-7.10 (m, 3H), 7.1-1.90 (m, 6H).

[0652] MS (thermospray): M/Z (MH⁺) 413.2; C₂₄H₃₂N₂O₂S+H requires 413.2.

EXAMPLE 107

[0653]

[0654] To a solution ofN-(3-{3-[3-(1H-indol-3-yl)propanoyl]-6-methyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 123, 135 mg, 0.34 mmol) in anhydrous tetrahydrofuran (2.5ml) under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.68 ml, 0.68 mmol)and the mixture was stirred at room temperature for 20 h. The rapidlystirred reaction mixture was treated sequentially with water (0.68 ml),sodium hydrogen carbonate (400 mg) and ethyl acetate (15 ml). After 30min the reaction mixture was filtered and concentrated in vacuo toafford a glassy oil. This was purified by preparative HPLC (condition 8)to give a light brown oil which was partitioned between dichloromethane(15 ml) and aqueous potassium carbonate solution (7% w:v, 5 ml). Thelayers were separated and the organic layer was washed with water (5ml), dried (MgSO₄), filtered and -concentrated in vacuo to afford thetitle compound as a colourless oil (69 mg, 50%).

[0655] NMR (CDCl₃, selected data for the free base): 1.57 (s, 3H), 1.80(m, 2H), 1.80-2.00 (m, 2H), 2.60 (m, 2H), 2.75-3.10 (m, 9H), 7.00-7.30(m, 7H), 7.35 (d, 1H), 7.60 (d, 1H), 7.95 (br., 1H).

[0656] MS (electrospray): M/Z (MH⁺) 424.2; C₂₄H₂₉N₃O₂S+H requires 424.2.

EXAMPLE 108

[0657]

[0658] To a solution ofN-(3-{6-methyl-3-[3-(4-pyridinyl)propanoyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 124, 100 mg, 0.25 mmol) in anhydrous tetrahydrofuran (2.5ml) under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.50 ml, 0.50 mmol)and the mixture was stirred at 10° C. for 2 h. The rapidly stirredreaction mixture was treated sequentially with water (0.40 ml), sodiumhydrogen carbonate (400 mg) and ethyl acetate (20 ml). After 18 h thereaction mixture was filtered and concentrated in vacuo to afford acolourless oil (70 mg). The free base was dissolved in anhydrous diethylether (5 ml) and dichloromethane (1 ml) and the solution was treatedwith hydrogen chloride (1.0M solution in diethyl ether, 0.18 ml). Excessdiethyl ether was decanted from the resulting precipitate and theremaining suspension was concentrated in vacuo to afford thehydrochloride salt of the title compound as a white solid (64 mg, 83%).

[0659] NMR (CD₃OD, selected data for the hydrochloride salt): 1.45 (br.,3H), 2.10 (m, 2H), 2.38 (m, 2H), 2.82 (m, 2H), 2.95 (m, 3H), 3.08 (m,1H), 3.22-3.40 (m, 4H), 4.05 (m, 1H), 7.05-7.15 (m, 2H), 7.20 (s, 1H),7.28 (dd, 1H), 7.50 (d, 2H), 8.55 (d, 2H).

[0660] MS (electrospray): M/Z (MH⁺) 386.2; C₂₁H₂₈N₃O₂S +H requires386.2.

EXAMPLE 109

[0661]

[0662] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 122 mg, 0.404 mmol) in N,N-dimethylformamide (4 ml) wasadded 2-(2-bromoethyl)naphthalene (A. K. Mitra, R. C. Bannerjee and R.Bhattacharya, J. Ind. Chem. Soc., 1971, 48, 391, 95 mg, 0.404 mmol) andsodium hydrogen carbonate (102 mg 1.212 mmol). The reaction mixture washeated at 80° C. for 6 h before allowing to cool to room temperature.The mixture was partitioned between water (5 ml) and dichloromethane (5ml), and the aqueous layer was extracted with dichloromethane (2×5 ml).The combined organic extracts were dried (Na₂S₄), filtered andconcentrated in vacuo to give a brown oil (130 mg). The residue waspurified by chromatography using a Biotage Flash 12™ cartridge packedwith silica gel (8 g) eluting with dichloromethane:ethanol:0.88 ammonia(400:8:1) to afford the title compound as a pale yellow oil. The freebase was dissolved in anhydrous diethyl ether (2 ml) and dichloromethane(0.5 ml) and the solution was treated with hydrogen chloride (1.0Msolution in diethyl ether, 0.15 ml). The resulting suspension wasconcentrated in vacuo to afford the hydrochloride salt of the titlecompound as a pale yellow solid (52 mg, 28%).

[0663] NMR (CD₃OD, for the hydrochloride salt): 1.28 (m, 2H), 1.50 (br.,3H), 2.38 (m, 2H), 2.95 (s, 3H), 3.10-3.25 (m, 3H), 3.55-3.65 (m, 3H),4.10 (br., 1H), 7.05-7.15 (m, 2H), 7.22-7.35 (m, 2H), 7.45-7.55 (m, 3H),7.80-7.92 (m, 4H).

[0664] MS (electrospray): M/Z (MH⁺) 421.2; C₂₅H₂₈N₂O₂S+H requires 421.2.

EXAMPLE 110

[0665]

[0666] To a solution ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamidehydrochloride salt (Preparation 53, 100 mg, 0.33 mmol) in ethyleneglycol dimethyl either (10 ml) was added sodium hydrogen carbonate (1.5g, 18 mmol) and 4-[(methylsulfonyl)amino]phenethyl methanesulfonate (P.E. Cross, J. E. Arrowsmith, G. N. Thomas, R. P. Dickinson, DD 281 599A5, 97 mg, 0.33 mmol) and the reaction mixture was heated at 60° C. for20 h. After cooling, diethyl ether (15 ml) and water (15 ml) were addedand the reaction mixture was stirred vigorously for 5 min. The phaseswere separated and the aqueous layer was further extracted with diethylether (2×10 ml). The combined organic extracts were dried (Na₂SO₄),filtered and concentrated in vacuo. The residual oil was purified byflash column chromatography using a Sep-Pak™ cartridge packed withsilica gel (10 g) eluting with dichloromethane:ethanol:0.88 ammoniasolution (200:8:1) to afford the title compound as an oil. The oil wasfurther purified by preparative HPLC (condition 9) to give the titlecompound as a colourless glass (11 mg, 7%).

[0667] NMR (CDCl₃, selected data for the free base): 0.8-1.0(m, 2H), 1.2(s, 3H), 1.5 (s, 6H), 1.9 (m, 1H), 2.8 (m, 2H), 3.0 (d, 6H), 3.1 (m,2H), 7.0-7.3 (m, 8H)

[0668] MS (thermospray): M/Z (MH⁺) 464.0, C₂₂H₂₉N₃O₄S₂+H requires 464.1.

EXAMPLE 111

[0669]

[0670] To a solution ofN-[3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Example 6, 132 mg, 0.39 mmol) in dichloromethane (12 ml) at 0° C. wasadded dropwise chlorine (0.132 M solution in acetic acid, 2.94 ml, 0.39mmol) over 30 min. The mixture was stirred for 3 h, slowly warming toroom temperature. The reaction mixture was basified to pH 8 by carefuladdition of saturated aqueous potassium carbonate solution and theresulting mixture was stirred at room temperature for 15 hours. Thelayers were separated and the aqueous layer was extracted withdichloromethane (2×15 ml). The combined organic extracts were dried(Na₂SO₄), filtered and concentrated in vacuo. The residual oil waspurified by chromatography using a Sep-Pak™ cartridge packed with silicagel (10 g) eluting with dichloromethane:ethanol:0.88 ammonia(100:2:1then 100:4:1) to give a mixture of two products. The twoproducts were separated by preparative HPLC (condition 10) to affordfirstly the title compound as a colourless glass (12 mg, 7%).

[0671] NMR (CDCl₃, selected data for the free base): 0.90 (m, 3H),1.20-1.40 (m, 7H), 1.40-1.50 (m, 4H), 1.75 (m, 2H), 2.40 (m, 2H), 2.80(m, 2H), 3.00-3.10 (m, 5H), 7.40 (s, 1H), 7.60 (s, 1H).

[0672] MS (electrospray): M/Z (MH⁺) 419.0; C₁₉H₂₈Cl₂N₂O₂S+H requires419.1.

EXAMPLE 112

[0673]

[0674] To a solution ofN-[3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Example 6, 132 mg, 0.39 mmol) in dichloromethane (12 ml) at 0° C. wasadded dropwise chlorine (0.132 M solution in acetic acid, 2.94 ml, 0.39mmol) over 30 min. The mixture was stirred for 3 h, slowly warming toroom temperature. The reaction mixture was basified to pH 8 by carefuladdition of saturated aqueous potassium carbonate solution and theresulting mixture was stirred at room temperature for 15 hours. Thelayers were separated and the aqueous layer was extracted withdichloromethane (2×15 ml). The combined organic extracts were dried(Na₂SO₄), filtered and concentrated in vacuo. The residual oil waspurified by chromatography using a Sep-Pak™ cartridge packed with silicagel (10 g) eluting with dichloromethane: ethanol:0.88 ammonia (100:2:1then 100:4:1) to give a mixture of two products. The two products wereseparated by preparative HPLC (condition 10) to afford firstlyN-[2,4-Dichloro-5-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamideas a colourless glass (Example 111, 12 mg, 7%). Further elution usingpreparative HPLC (condition 10) afforded the title compound as acolourless glass (11 mg, 7%).

[0675] NMR (CDCl₃, selected data for the free base): 0.90 (m, 3H),1.20-1.40 (m, 7H), 1.40-1.50 (m, 4H), 1.75 (m, 1H), 1.85 (m, 1H), 2.45(m, 2H), 2.80 (m, 2H), 3.00 (m, 3H), 3.10 (m, 1H), 7.25 (d, 1H).

[0676] MS (electrospray): M/Z (MH³⁰ ) 419.0; C₁₉H₂₈Cl₂N₂O₂S+H requires419.1.

EXAMPLE 113

[0677]

[0678] To a solution ofN-(3-{6-methyl-3-[3-(2-thienyl)propanoyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 125, 200 mg, 0.49 mmol) in anhydrous tetrahydrofuran (7.5ml) under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.99 ml, 0.99 mmol)and the mixture was stirred at room temperature for 2 h. The rapidlystirred reaction mixture was treated sequentially with water (1.0 ml),sodium hydrogen carbonate (1.0 g) and ethyl acetate (25 ml). After 15min the reaction mixture was filtered and concentrated in vacuo toafford a light yellow oil. This was purified by chromatography using aBiotage Flash 12™ cartridge packed with silica gel (8 g) eluting withhexane:ethyl acetate (100:0 to 0:100) to afford the title compound as acolourless oil (135 mg, 70%).

[0679] NMR (CDCl₃, selected data for the free base): 1.55 (s, 3H),1.75-1.90 (m, 4H), 2.50-2.70 (m, 2H), 2.85-3.10 (m, 9H), 6.80 (m, 1H),6.95 (m, 1H), 7.00-7.15 (m, 4H), 7.20-7.30 (m, 1H).

[0680] MS (electrospray): M/Z (MH⁺) 391.1; C₂₀H₂₆N₂O₂S₂+H requires391.1.

EXAMPLE 114

[0681]

[0682] To a solution ofN-(3-{6-methyl-3-[3-(3-thienyl)propanoyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 126, 200 mg, 0.49 mmol) in anhydrous tetrahydrofuran (7.5ml) under a nitrogen atmosphere at 0° .C was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.99 ml, 0.99 mmol)and the mixture was stirred at room temperature for 2 h. The rapidlystirred reaction mixture was treated sequentially with water (1 ml),sodium hydrogen carbonate (1.0 g) and ethyl acetate (25 ml). After 15min the reaction mixture was filtered and concentrated in vacuo toafford a light yellow oil. This was purified by chromatography using aBiotage Flash 12™ cartridge packed with silica gel (8 g) eluting withhexane:ethyl acetate (100:0 to 0:100) to afford the title compound as acolourless oil (108 mg, 56%).

[0683] NMR (CDCl₃, selected data for the free base): 1.55 (s, 3H),1.70-1.90 (m, 4H), 2.45-2.60 (m, 2H), 2.70 (m, 2H), 2.80-3.10 (m, 7H),6.95 (d, 2H), 7.00-7.15 (m, 3H), 7.20-7.30 (m, 2H).

[0684] MS (electrospray): M/Z (MH⁺) 391.1; C₂₀H₂₆N₂O₂S₂+H requires391.1.

EXAMPLE 115

[0685]

[0686] A solution of[6-3-aminophenyl)-3-hexyl-3-azabicyclo[3.1.0]hex-6-yl]methanol(Preparation 94, 0.03 g, 0.09 mmol) in tetrahydrofuran (1 ml) wasstirred at 0° C. under an atmosphere of nitrogen. The reaction mixturewas treated with triethylamine (0.03 ml, 0.19 mmol) followed by dropwiseaddition of methyl chloroformate (0.01 ml, 0.17 mmol). The reactionmixture was allowed to warm to room temperature and stirred for 2 hbefore pouring onto aqueous saturated sodium hydrogen carbonate (50 ml).The product was extracted with ethyl acetate (3×25 ml) and the combinedorganic extracts were dried (Na₂SO₄) and then concentrated in vacuo togive a brown residue. The crude product was purified by preparative HPLC(condition 11) to give a clear glass (6 mg, 15% yield).

[0687] NMR (CD₃OD, selected data for the free base): 1.55 (m, 2H), 2.10(m, 1H), 3.55 (m, 2H), 3.70 (s, 3H), 3.75 (s, 3H), 4.0-4.15 (m, 3H),4.25 (m, 1H), 6.85 (d, 1H), 7.19-7.35 (m, 3H).

EXAMPLE 116

[0688]

[0689] To a suspension ofN-{3-[3-(1-benzofuran-2-ylcarbonyl)-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide(Preparation 127, 200 mg, 0.487 mmol) in anhydrous tetrahydrofuran (5ml) under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.97 ml, 0.97 mmol)and the reaction mixture was stirred at room temperature overnight. Therapidly stirred reaction mixture was treated sequentially with water(1.0 ml), sodium hydrogen carbonate (1.0 g) and ethyl acetate (15 ml).After 5 min, the reaction mixture was filtered and concentrated in vacuoto afford 180 mg of a pale yellow oil. This was purified bychromatography using a Biotage Flash 12™ cartridge packed with silicagel (8 g) eluting with hexane:ethyl acetate (100:0 to 0:100 over 30 min)then ethyl acetate:methanol (100:0 to 0:100 over 15 min) to afford thetitle compound as a white foam (136 mg, 70%).

[0690] NMR (CDCl₃, selected data for the free base): 1.55 (s, 03H), 1.83(m, 2H), 3.00 (s, 3H), 3.05-3.20 (m, 4H), 3.88 (m, 2H), 6.40-6.70 (m,2H), 7.00-7.13 (m, 31), 7.18-7.35 (m, 2H), 7.45 (d, 1H), 7.55 (d, 1H).

[0691] MS (electrospray): M/Z (MH⁺) 397.4; C₂₂H₂₄N₂O₃S+H requires 397.2.

EXAMPLE 117

[0692]

[0693] To a solution ofN-(3-{3-[3-(5-fluoro-3-methyl-1H-indol-2-yl)propanoyl]-6-methyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 128, 100 mg, 0.213 mmol) in anhydrous tetrahydrofuran (2.5ml) under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.42 ml, 0.42 mmol)and the reaction mixture was stirred at room temperature overnight. Therapidly stirred reaction mixture was treated sequentially with water(0.45 ml), sodium hydrogen carbonate (450 mg) and ethyl acetate (10 ml).After 5 min, the reaction mixture was filtered and concentrated in vacuoto afford 95 mg of a colourless oil. This was purified by chromatographyusing a Biotage Flash 12™ cartridge packed with silica gel (8 g) elutingwith hexane:ethyl acetate (100:0 to 0:100 over 30 min) then ethylacetate:methanol (100:0 to 0:100 over 15 min) to afford the titlecompound as a white foam (56 mg, 46%).

[0694] NMR (CDCl₃, selected data for the free base): 1.55 (s, 3H),1.80-1.93 (m, 4H), 2.20 (s, 3H), 2.59 (t, 2H), 2.83 (t, 2H), 3.00-3.10(m, 7H), 6.83 (ddd, 1H), 7.00-7.15 (m, 4H), 1.78 (dd, 1H), 7.24 (m, 1H).

[0695] MS (electrospray): M/Z (MH⁺) 456.2; C₂₅H₃₀FN₃O₂S+H requires456.2.

EXAMPLE 118

[0696]

[0697] To a solution ofN-(3-{6-methyl-3-[3-(2-pyridinyl)propanoyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 129, 16 mg, 0.04 mmol) in anhydrous tetrahydrofuran (2 ml)under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.01 M solution in tetrahydrofuran, 80 μl, 80 mmol)and the reaction mixture was stirred at room temperature for 5 h. Therapidly stirred reaction mixture was treated sequentially with water(100 μl), sodium carbonate (100 mg) and ethyl acetate (5 ml). After 5min, the reaction mixture was filtered and concentrated in vacuo toafford 10 mg of a colourless oil. This was purified by chromatographyusing silica gel (1 g) eluting with dichloromethane:ethanol:0.880ammonia (200:8:1) to afford the title compound as a colourless oil (3mg, 19%).

[0698] NMR (CDCl₃, selected data for the free base): 1.55 (s, 3H), 1.75(m, 2H), 1.90 (t, 2H), 2.50 (t, 2H), 2.75-2.88 (m, 4H), 3.00 (s, 3H),3.05 (d, 2H), 7.00 (d, 1H), 7.05-7.30 (m, 5H), 7.60 (d, 1H), 8.55 (d,1H).

[0699] MS (electrospray): M/Z (MH⁺) 386.2; C₂₁H₂₃N₂O₂S+H requires 386.2.

EXAMPLE 119

[0700]

[0701] To a solution ofN-(3-{6-methyl-3-[3-(3-methyl-2-thienyl)propanoyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 130, 150 mg, 0.358 mmol) in anhydrous tetrahydrofuran (10ml) under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.72 ml, 0.72 mmol)and the reaction mixture was stirred at room temperature overnight. Therapidly stirred reaction mixture was treated sequentially with water(0.75 ml), sodium hydrogen carbonate (750 mg) and ethyl acetate (15 ml).After 15 min, the reaction mixture was filtered and concentrated invacuo to afford 140 mg of a colourless oil. This was purified bychromatography using a Biotage Flash 12™ cartridge packed with silicagel (8 g) eluting with hexane:ethyl acetate (100:0 to 0:100 over 30 min)and then with ethyl acetate:methanol (100:0 to 0:100 over 5 min) toafford the title compound as a colourless oil (74 mg, 50%).

[0702] NMR (CDCl₃, selected data for the free base): 1.57 (s, 3H),1.75-1.90 (m, 4H), 2.18 (s, 3H), 2.58 (m, 2H), 2.79 (t, 2H), 2.82-3.12(m, 7H), 6.78 (d, 1H), 7.00-7.15 (m, 4H), 7.25 (m, 1H).

[0703] MS (electrospray): M/Z (MH⁺) 405; C₂₁H₂₈N₂O₂S₂ +H requires 405.

EXAMPLE 120

[0704]

[0705] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 450 mg, 1.50 mmol) in N,N-dimethylformamide (20 ml) wasadded sodium hydrogen carbonate (375 mg, 4.50 mmol),1-(3-chloropropyl)-4-methoxybenzene (274 mg, 1.50 mmol) and sodiumiodide (35 mg) and the reaction was heated at 55° C. for 3 d. Thereaction mixture was concentrated in vacuo and the residue was treatedwith water (15 ml) and extracted with ethyl acetate (2×20 ml). Thecombined organic extracts were washed with water (15 ml), dried (MgSO₄),filtered and concentrated in vacuo to afford 570 mg of a brown gum. Thiswas purified by chromatography using a Biotage Flash 12™ cartridgepacked with silica gel (8 g) eluting with dichloromethane:ethanol:0.880ammonia (250:8:1) to afford the title compound as a colourless oil (37mg, 6%).

[0706] NMR (CDCl₃, selected data for the free base): 1.55 (s, 3H),1.70-1.85 (m, 4H), 2.52 (t, 2H), 2.60 (t, 2H), 2.83-3.08 (m, 7H), 3.80(s, 3H), 6.82 (d, 2H), 7.00-7.15 (m, 5H), 7.24 (dd, 1H).

[0707] MS (thermospray): M/Z (MH⁺) 415; C₂₃H₃₀N₂O₃S+H requires 415.

EXAMPLE 121

[0708]

[0709] To a solution ofN-(3-{3-[3-(2-chlorophenyl)propanoyl]-6-methyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 131, 100 mg, 0.231 mmol) in anhydrous tetrahydrofuran (2.5ml) under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.25 ml, 0.25 mmol)and the reaction mixture was stirred at room temperature for 7 h. Therapidly stirred reaction mixture was treated sequentially with water(0.25 ml), sodium carbonate (250 mg) and ethyl acetate (2.5 ml). Thereaction mixture was left to stir overnight and then was filtered andconcentrated in vacuo. This was purified by chromatography using silicagel (2 g) eluting with ethyl:acetate:hexane:0.880 ammonia (60:40 1) toafford the title compound as a colourless oil (77 mg, 80%).

[0710] NMR (CDCl₃, selected data): 1.58 (s, 3H), 1.70-1.80 (m, 4H), 2.52(t, 2H), 2.65-2.82 (m, 4H), 3.00 (s, 3H), 3.03 (d, 2H), 7.00-7.38 (m,8H).

[0711] MS (electrospray): M/Z M+H⁺) 419.2; C₂₂H₂₇ClN₂ ₂S+H requires419.2.

[0712] IR ?_(max) (polyethylene card)/cm⁻¹: 1607 (w), 1472 (w), 1325(m), 1156 (s).

EXAMPLE 122

[0713]

[0714] To a solution ofN-(3-{6-methyl-3-[(E)-3-(3-thienyl)-2-propanoyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 132, 100 mg, 0.248 mmol) in anhydrous tetrahydrofuran (2.5ml) under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.25 ml, 0.25 mmol)and the reaction mixture was stirred at room temperature for 7 h. Therapidly stirred reaction mixture was treated sequentially with water(0.25 ml), sodium carbonate (250 mg) and ethyl acetate (2.5 ml). Thereaction mixture was left to stir overnight and then was filtered andconcentrated in vacuo. This was purified by chromatography using silicagel (2 g) eluting with ethyl acetate:hexane:0.880 ammonia (60:40:1) toafford the title compound as a colourless oil (32 mg, 33%).

[0715] NMR (CDCl₃, selected data): 1.58 (s, 3H), 1.78 (m, 2H), 2.42-2.95(m, 2H), 3.00-3.10 (m, 5H), 3.25 (d, 2H), 6.05 (dt, 1H), 6.55 (d, 1H),6.92-7.15 (m, 5H), 7.20-7.30 (m, 2H).

[0716] MS (electrospray): M/Z (MH⁺) 389.1; C₂₀H₂₄N₂O₂S₂+H requires389.1.

[0717] IR ?_(max) (polyethylene card)/cm⁻¹: 1607 (w), 1472 (w), 1325(m), 1155 (s), 971 (m).

EXAMPLE 123

[0718]

[0719] To a solution ofN-(3-{6-methyl-3-[(E)-3-(2-thienyl)-2-propenoyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 133, 100 mg, 0.248 mmol) in anhydrous tetrahydrofuran (2.5ml) under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.25 ml, 0.25 mmol)and the reaction mixture was stirred at room temperature for 7 h. Therapidly stirred reaction mixture was treated sequentially with water(0.25 ml), sodium carbonate (250 mg) and ethyl acetate (2.5 ml). Thereaction mixture was left to stir overnight and then was filtered andconcentrated in vacuo. This was purified by chromatography using silicagel (2 g) eluting with ethyl acetate:hexane:0.880 ammonia (60:40:1) toafford the title compound as a pale yellow oil (67 mg, 69%).

[0720] NMR (CDCl₃, selected data): 1.58 (s, 3H), 1.80 (m, 2H), 2.95 (m,2H), 3.00 (s, 3H), 3.04 (d, 2H), 3.23 (d, 2H), 6.10 (dt, 1H), 6.65 (d,1H), 6.92-6.98 (m, 2H), 7.00-7.15 (m, 4H), 7.23 (m, 1H).

[0721] MS (electrospray): M/Z (M+H⁺) 389.1; C₂₀H₂₄N₂O₂S₂+H requires389.1.

[0722] IR ?_(max) (polyethylene card)/cm⁻¹: 1607 (w), 1472 (w), 1325(m), 1155 (s), 974 (m).

EXAMPLE 124

[0723]

[0724] To a solution ofN-(3-{6-methyl-3-[(E)-3-(3-methyl-2-thienyl)-2-propenoyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 134, 100 mg, 0.240 mmol) in anhydrous tetrahydrofuran (2.5ml) under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.25 ml, 0.25 mmol)and the reaction mixture was stirred at room temperature for 7 h. Therapidly stirred reaction mixture was treated sequentially with water(0.25 ml), sodium carbonate (250 mg) and ethyl acetate (2.5 ml). Thereaction mixture was left to stir overnight and then was filtered andconcentrated in vacuo. This was purified by chromatography using silicagel (2 g) eluting with ethyl acetate:hexane:0.880 ammonia (60:40:1) toafford the title compound as a very pale yellow oil (60 mg, 62%).

[0725] NMR (CDCl₃, selected data): 1.58 (s, 3H), 1.78 (m, 2H), 2.02 (s,3H), 2.90 (m, 2H), 3.00 (s, 3H), 3.05 (d, 2H), 3.27 (d, 2H), 6.00(dt,1H), 6.65 (d, 1H), 6.78 (d, 1H), 7.00-7.05 (m, 2H), 7.05-7.10 (m,2H), 7.25 (m, 1H).

[0726] MS (electrospray): M/Z (M+H⁺) 403.2; C₂₁H₂₆N₂O₂S₂+H requires403.2.

[0727] IR ?_(max) (polyethylene card)/cm⁻¹: 2360 (m), 1607 (w), 1472(w), 1325 (m), 1155 (s), 975 (m).

EXAMPLE 125

[0728]

[0729] To a solution of2-[3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation140, 30 mg, 0.11 mmol) in pyridine (1.0 ml) under a nitrogen atmosphereat room temperature was added dropwise methane sulfonyl chloride (13 μl,0.16 mmol), and the reaction mixture was stirred at room temperature for2 d. Ice (2 g) and dichloromethane (5 ml) were added, the layers wereseparated and the aqueous layer was further extracted withdichloromethane (5 ml). The combined extracts were dried (Na₂SO₄),filtered and concentrated in vacuo. This was purified by chromatographyusing silica gel (1.5 g) eluting with dichloromethane:ethanol:0.880ammonia (200:8:1) to afford the title compound as a very pale yellow oil(5.2 mg, 14%).

[0730] NMR (CDCl₃, selected data): 0.88 (m, 3H), 1.20-1.40 (m, 6H), 2.18(d, 1H), 2.40 (d, 1H), 3.15-3.30 (m, 4H), 3.38 (m, 1H), 7.14 (dd, 1H),7.23 (s, 1H), 7.32 (dd, 1H), 7.55 (d, 1H).

EXAMPLE 126

[0731]

[0732] To a solution of3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine(Preparation 8, 1.00 g, 3.26 mmol) in acetone (5 ml) at 0° C. was addedmethanesulfonyl chloride (0.28 ml, 3.58 mmol) and the reaction mixturewas stirred at room temperature overnight. The resulting precipitate wascollected by filtration to afford the title compound as a whitecrystalline solid (1.19 g, 87%).

[0733] Melting point 212-214° C.

[0734] MS (APCI): M/Z (MH⁺) 385.8; C₂₂H₂₈N₂O₂S+H requires 385.2.

EXAMPLE 127

[0735]

[0736] A solution ofN-(3-{6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Example 1, 53.88 g, 0.14 mol) in 2-butanone (480 ml) was heated underreflux. To the solution was added a solution of benzenesulfonic acid(22.17 g, 0.14 mol) in 2-butanone (50 ml) and the reaction mixture washeated under reflux for 30 min before cooling to 10° C. over a 2 hperiod. The resulting precipitate was collected by filtration to affordthe title compound as a beige crystalline solid (73.55 g, 97%).

[0737] Melting point 166-168° C.

[0738] MS (APCI): M/Z (MH⁺) 385.7; C₂₂H₂₈N₂O₂S+H requires 385.2.

EXAMPLE 128

[0739]

[0740] A solution ofN-(3-{6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Example 1, 25.00 g, 65 mmol) in ethyl acetate (250 ml) was heated underreflux. To the solution was added para-toluenesulfonic acid (12.36 g, 72mmol) and the reaction mixture was heated under reflux for 60 min beforecooling to 10° C. over a 2 h period. The resulting precipitate wascollected by filtration to afford the title compound as a white solid(35.46 g, 95%).

[0741] Melting point 182-184° C.

[0742] MS (APCI): M/Z (MH⁺) 385.3; C₂₂H₂₈N₂O₂S+H requires 385.2.

EXAMPLE 129

[0743]

[0744] A solution ofN-(3-{6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Example 1, 2.00 g, 5.2 mmol) in Industrial Methylated Spirits (20 ml)was heated under reflux. To the solution was added L-tartaric acid (0.86g, 5.8 mmol) and the reaction mixture was heated under reflux for 30 minbefore cooling to 10° C. over a 2 h period. The resulting precipitatewas collected by filtration to afford the title compound as a whitesolid (1.40 g, 50%/).

[0745] Melting point 162-164° C.

[0746] MS (APCI): M/Z (MH⁺) 385.5; C₂₂H₂₈N₂O₂S+H requires 385.2.

EXAMPLE 130

[0747]

[0748] A solution ofN-(3-{6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Example 1, 2.00 g, 5.2 mmol) in Industrial Methylated Spirits (20 ml)was heated under reflux. To the solution was added succinic acid (0.68g, 5.8 mmol) and the reaction mixture was heated under reflux for 30 minbefore cooling to 10° C. over a 2 h period. The resulting precipitatewas collected by filtration to afford the title compound as a whitesolid (1.42 g, 54%).

[0749] Melting point 162-164° C.

[0750] MS (APCI): M/Z (MH⁺) 385.4; C₂₂H₂₈N₂O₂S+H requires 385.2.

EXAMPLE 131

[0751] Formulation of N-(3-{6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide A compositionsuitable for intravenous administration is as follows:-N-(3-{6-Methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6- 45 mgyl}phenyl)methanesulfonamide acetate salt (Example 2) Dimethylsulfoxide2.02 ml 0.9% w:v Aqueous sodium chloride solution 42.98 ml

EXAMPLE 132

[0752] Formulation of N-(3-{6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide A compositionsuitable for oral capsule administration is as follows:N-(3-{6-Methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6- 59.4 mgyl}phenyl)methanesulfonamide hydrochloride salt (Example 126)Tetragylcol 2.715 ml Polyethyleneglycol 400 2.715 ml

[0753] A suspension ofN-(3-{6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamidehydrochloride salt (Example 126) in 50:50 tetragylcol:polyethyleneglycol 400 was placed on a Denley Spiromix 5™ overnight to afford asolution. The solution was placed in a hard gelatin capsule shell, size0, and the capsule lid was placed on the capsule body and sealed tight.

EXAMPLE 133

[0754] Formulation of N-(3-{6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide A compositionsuitable for oral gavage administration is as follows:N-(3-{6-Methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6- 140 mgyl}phenyl)methanesulfonamide para-toluenesulfonate salt (Example 128)Propylene glycol 70 ml

EXAMPLE 134

[0755] Formulation of N-(3-{3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide A compositionsuitable for oral gavage administration is as follows:N-(3-{3-Hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)- 80 mgmethanesulfonamide hydrochloride salt (Example 6) Propylene glycol 40 ml

EXAMPLE 135

[0756] Formulation of N-(3-{3-(3-cyclohexylpropyl)-6-methyl-3-azabicyclo[3.1.0]hex-6- yl}phenyl)ethanesulfonamide Acomposition suitable for oral gavage administration is as follows:N-(3-{3-(3-Cyclohexylpropyl)-6-methyl-3-azabicyclo[3.1.0]hex- 70 mg6-yl}phenyl)ethanesulfonamide hydrochloride salt (Example 5) Water 35 ml

EXAMPLE 136

[0757]

[0758] To a solution ofN-(3-{6-methyl-3-[(E)-3-(2-pyridinyl)-2-propenoyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 141, 172 mg, 0.43 mmol) in anhydrous tetrahydrofuran (2.5ml) under a nitrogen atmosphere at room temperature was added dropwiselithium aluminium hydride (1.0M solution in tetrahydrofuran, 0.50 ml,0.50 mmol) and the reaction mixture was stirred at room temperature for2 h. The rapidly stirred reaction mixture was treated sequentially withwater (0.5 ml), sodium carbonate (0.5 g) and ethyl acetate (5 ml). Thereaction mixture was left to stir for 1 h 30 min, filtered, solid washedwith methanol (5 ml) and combined filtrate concentrated using a streamof nitrogen to afford 215 mg of a pale brown oil. This was purified bychromatography using a Biotage Flash 40S™ cartridge packed with silicagel (40 g) eluting with dichloromethane:ethanol:0.880 ammonia (300:8:1)to afford the title compound as a pale brown oil (78 mg, 47%).

[0759] NMR (CDCl₃, selected data): 1.58 (s, 3H), 1.78 (br. s, 2H), 2.90(br. d, 2H), 3.00 (s, 3H), 3.12 (d, 2H), 3.37 (d, 2H), 6.60-6.70 (m,2H), 7.00 (d, 1H), 7.05-7.15 (m, 3H), 7,20-7,35 (m, 2H), 7.62 (dd, 1H),8.57 (d, 1H).

[0760] MS (electrospray): M/Z (MH⁺) 384.3; C₂₁H₂₅N₃O₂S+H requires 384.2.

EXAMPLE 137

[0761]

[0762] To a solution ofN-(3-{6-methyl-3-[(E)-3-(2-quinolinyl)-2-propenoyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 142, 206 mg, 0.46 mmol) in anhydrous tetraydroflra (2.5 ml)under a nitrogen atmosphere at room temperature was added dropwiselithium aluminium hydride (1.0M solution in tetrahydrofuran, 0.50 ml,0.50 mmol) and the reaction mixture was stirred at room temperature for2 h. The rapidly stirred reaction mixture was treated sequentially withwater (0.5 ml), sodium carbonate (0.5 g) and ethyl acetate (5 ml). Thereaction mixture was left to stir for 1 h 30 min, filtered, solid washedwith methanol (5 ml) and combined filtrate concentrated using a streamof nitrogen to afford 221 mg of a pale brown oil. This was purified bychromatography using a Biotage Flash 40S™ cartridge packed with silicagel (40 g) eluting with dichloromethane:ethanol:0.880 ammonia (300:8:1)to afford the title compound as a dark yellow oil (84 mg, 42%).

[0763] NMR (CDCl₃, selected data): 1.58 (s, 3H), 1.79 (br. s, 2H), 2.92(d, 2H), 3.00 (s, 3H), 3.13 (d, 2H), 3.42 (d, 2H), 6.80-6.88 (m, 2H),7.00 (d, 1H), 7.05-7.10 (m, 2H), 7.23 (m, 1H), 7.47 (dd, 1H), 7.56 (d,1H), 7.68 (dd, 1H), 7.75 (d, 1H), 8.05 (d, 1H), 8.10 (d, 1H).

[0764] MS (electrospray): M/Z (MH⁺) 434.3; C₂₅H₂₇N₃O₂S+H requires 434.2.

EXAMPLE 138

[0765]

[0766] To a solution ofN-(3-{3-[3-(1,3-benzothiazol-2-yl)propanoyl]-6-methyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 143, 228 mg, 0.50 mmol) in anhydrous tetrahydrofuran (2.5ml) under a nitrogen atmosphere at room temperature was added dropwiselithium aluminium hydride (1.0M solution in tetaydrofuran, 0.50 ml, 0.50mmol) and the reaction mixture was stirred at room temperature for 2 h.The rapidly stirred reaction mixture was treated sequentially with water(0.5 ml), sodium carbonate (0.5 g) and ethyl acetate (5 ml). Thereaction mixture was left to stir for 1 h 30 min, filtered, solid washedwith methanol (5 ml) and combined filtrate concentrated using a streamof nitrogen to afford 650 mg of a pale brown oil. This was purified bychromatography using a Biotage Flash 40S™ cartridge packed with silicagel (40 g) eluting with dichloromethane:ethanol:0.880 ammonia (300:8:1)to afford the title compound as a yellow oil (198 mg, 90%).

[0767] NMR (CDCl₃, selected data): 1.58 (s, 3H), 1.76 (m, 2H), 2.02 (dd,2H), 2.60 (dd, 2H), 2.80 (br. d, 2H), 3.00 (s, 3H), 3.10 (d, 2H), 3.16(dd, 2H), 7.00 (d, 1H), 7.05-7.10 (m, 2H), 7.23 (m, 1H), 7.35 (dd, 1H),7.45 (dd, 1H), 7.83 (d, 1H), 7.96 (d, 1H).

[0768] MS (electrospray): M/Z (MH⁺) 442.3; C₂₃H₂₇N₃O₂S+H requires 442.2.

EXAMPLE 139

[0769]

[0770] To a solution ofN-(3-{6-methyl-3-[(E)-3-(6-methyl-2-pyridinyl)-2-propenoyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 144, 191 mg, 0.46 mmol) in anhydrous tetrahydrofuran (2.5ml) under a nitrogen atmosphere at room temperature was added dropwiselithium aluminium hydride (1.0M solution in tetrahydrofuran, 0.50 ml,0.50 mmol) and the reaction mixture was stirred at room temperature for2 h. The rapidly stirred reaction mixture was treated sequentially withwater (0.5 ml), sodium carbonate (0.5 g) and ethyl acetate (5 ml). Thereaction mixture was left to stir for 1 h 30 min, filtered, solid washedwith methanol (5 ml) and combined filtrate concentrated using a streamof nitrogen to afford 221 mg of a dark yellow oil. This was purified bychromatography using a Biotage Flash 40S™ cartridge packed with silicagel (40 g) eluting with dichloromethane:ethanol:0.880 ammonia (300:8:1)to afford the title compound as a pale brown oil (102 mg, 56%).

[0771] NMR (CDCl₃, selected data): 1.58 (s, 3H), 1.78 (br. s, 2H), 2.55(s, 3H), 2.90 (d, 2H), 3.00 (s, 3H), 3.08 (d, 2H), 3.35 (d, 2H),6.63-6.69 (m, 2H), 6.97-7.03 (m, 2H), 7.05-7.10 (m, 2H), 7.15 (d, 1H),7.23 (m, 1H), 7.53 (dd, 1H).

[0772] MS (electrospray): M/Z (MH⁺) 398.3; C₂₂H₂₇N₃O₂S+H requires 398.2.

EXAMPLE 140

[0773]

[0774] To a solution ofN-[3-(6-methyl-3-{(E)-3-[2-(trifluoromethyl)phenyl]-2-propenoyl}-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 145, 240 mg, 0.52 mmol) in anhydrous tetrahydrofuran (2.5ml) under a nitrogen atmosphere at room temperature was added dropwiselithium aluminium hydride (1.0M solution in tetrahydrofuran, 0.55 ml,0.55 mmol) and the reaction mixture was stirred at room temperature for5 h. A further addition of lithium aluminium hydride (1.0M solution intetrahydrofuran, 0.50 ml, 0.50 mmol) was made dropwise and the reactionmixture was left a further 30 min. The rapidly stirred reaction mixturewas treated sequentially with water (1.0 ml), sodium carbonate (1.0 g)and ethyl acetate (5 ml). The reaction mixture was left to stir for 1 h30 min, filtered, solid washed with methanol (5 ml) and combinedfiltrate concentrated using a stream of nitrogen to afford 689 mg of apale yellow oil. This was purified by chromatography using a BiotageFlash 40S™ cartridge packed with silica gel (40 g) eluting withdichloromethane:ethanol:0.880 ammonia (600:8:1) to afford the titlecompound as a pale yellow oil (77 mg, 33%).

[0775] NMR (CDCl₃, selected data): 1.58 (s, 3H), 1.76 (m, 2H), 2.55 (dd,1H), 2.80 (dd, 1H), 2.88 (d, 1H), 3.00 (s, 3H), 3.07-3.13 (m, 2H), 3.33(d, 1H), 6.22 (ddd, 1H), 6.95 (d, 1H), 7.02 (d, 1H), 7.05-7.12 (m, 2H),7.24-7.28 (m, 2H), 7.33 (dd, 1H), 7.49 (dd, 1H) 7.62 (d, 1H).

[0776] MS (electrospray): M/Z (MH⁺) 451.4; C₂₃H₂₅ ¹⁹F₃N₂O₂S+H requires451.2.

EXAMPLE 141

[0777]

[0778] To a solution of the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 226 mg, 0.746 mmol) in N,N-dimethylformamide (10 ml)was added 2-(3-bromopropyl)-1,3-dichlorobenzene (J. Augstein et al., J.Med. Chem., 1967, 10, 391; 200 mg, 0.746 mmol) and sodium hydrogencarbonate (187 mg 2.238 mmol). The reaction mixture was heated at 80° C.for overnight before allowing to cool to room temperature. The mixturewas concentrated in vacuo and the residue was partitioned between water(10 ml) and ethyl acetate (15 ml). The organic extract was dried(Na₂SO₄), filtered and concentrated in vacuo to give a brown oil (325mg). The residue was purified by silica (5 g) gel chromatography elutingwith dichloromethane:ethanol:0.880 ammonia (250:8:1) to afford the titlecompound as a pale yellow oil (42 mg, 13%).

[0779] NMR (CDCl₃, selected data for the free base): 1.58 (s, 3H),1.65-1.80 (m, 4H), 2.60 (t, 2H), 2.85 (br. m, 2H), 2.97 (d, 2H), 3.00(s, 3H), 3.15 (d, 2H), 7.00-7.15 (m, 4H), 7.22-7.30 (m, 3H).

[0780] MS (electrospray): M/Z (MH⁺) 453; C₂₂H₂₆Cl₂N₂O₂S+H requires 453.

EXAMPLE 142

[0781]

[0782] To a solution ofN-{3-[6-methyl-3-(4-phenylbutanoyl)3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide(Preparation 146, 100 mg, 0.24 mmol) in anhydrous tetrahydrofuran (2.5ml) under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.48 ml, 0.48 mmol)and the reaction mixture was stirred at room temperature overnight. Therapidly stirred reaction mixture was treated sequentially with water(0.48 ml), sodium carbonate (500 mg) and ethyl acetate (10 ml). Thereaction mixture was left to stir for 15 min, filtered, solid washedwith ethyl acetate (10 ml) and combined filtrate concentrated in vacuoto afford 102 mg of a pale yellow oil. The residue was purified bysilica (4 g) gel chromatography eluting withdichloromethane:ethanol:0.880 ammonia (250:8:1) to afford the titlecompound as a pale yellow oil (80 mg, 84%).

[0783] NMR (CDCl₃, selected data): 1.45-1.58 (m, 5H), 1.66 (dd, 2H),1.75 (m, 2H), 2.48 (t, 2H), 2.63 (t, 2H), 2.80 (br. d, 2H), 2.95-3.00(m, 5H), 7.00-7.12 (m, 3H), 7.15-7.32 (m, 6H).

[0784] MS (electrospray): M/Z (MH⁺) 398.8; C₂₃H₃₀N₂O₂S+H requires 399.2.

EXAMPLE 143

[0785]

[0786] To a solution ofN-(3-{3-[3-(2-methoxyphenyl)propanoyl]-6-methyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide(Preparation 147, 100 mg, 0.234 mmol) in anhydrous tetrahydrofuran (2.5ml) under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.47 ml, 0.47 mmol)and the reaction mixture was stirred at room temperature overnight. Therapidly stirred reaction mixture was treated sequentially with water(0.47 ml), sodium carbonate (500 mg) and ethyl acetate (10 ml). Thereaction mixture was left to stir for 15 min, filtered, solid washedwith ethyl acetate (10 ml) and combined filtrate concentrated in vacuoto afford 103 mg of a pale yellow oil. The residue was purified bysilica (4 g) gel chromatography eluting withdichloromethane:ethanol:0.880 ammonia (250:8:1) to afford the titlecompound as a colourless oil (86 mg, 89%).

[0787] NMR (CDCl₃, selected data): 1.55 (s, 3H), 1.70-1.85 (m, 4H), 2.50(t, 2H), 2.65 (t, 2H), 2.80 (m, 2H), 3.00-3.10 (m, 5H), 3.80 (s, 3H),6.80-6.95 (m, 2H), 7.00-7.30 (m, 6H).

[0788] MS (thermospray): M/Z (MH⁺) 415.1; C₂₃H₃₀N₂O₃S+H requires 415.2.

EXAMPLE 144

[0789]

[0790] To a solution ofN-{3-[3-(1-benzothiophen-2-ylcarbonyl)-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide(Preparation 148, 100 mg, 0.235 mmol) in anhydrous tetrahydrofuran (2.5ml) under a nitrogen atmosphere at 0° C. was added dropwise lithiumaluminium hydride (1.0M solution in tetrahydrofuran, 0.47 ml, 0.47 mmol)and the reaction mixture was stirred at room temperature overnight. Therapidly stirred reaction mixture was treated sequentially with water(0.47 ml), sodium carbonate (500 mg) and ethyl acetate (10 ml). Thereaction mixture was left to stir for 15 min, filtered, solid washedwith ethyl acetate (10 ml) and combined filtrate concentrated in vacuoto afford 104 mg of a light yellow oil. The residue was purified bysilica (4 g) gel chromatography eluting with hexane:ethyl acetate:0.880ammonia (50:50:1) to afford the title compound as a colourless oil (74mg, 76%).

[0791] NMR (CDCl₃, selected data) 1.60 (s, 3H), 1.80 (br. s, 2H), 2.88(m, 2H), 3.00 (s, 3H), 3.98 (br. s, 2H), 7.00-7.20 (m, 3H), 7.25-7.40(m, 4H), 7.70 (d, 1H), 7.80 (d, 1H).

[0792] MS (electrospray): M/Z (MH⁺) 413.2; C₂₂H₂₄N₂O₂S₂+H requires413.1.

[0793] Preparation 1

Ethyl (E)-3-(3-nitrophenyl)-2-butenoate

[0794] To a solution of sodium hydride (60% dispersion in oil, 20 g, 0.5mol) in tetrahydrofuran (1 l) stirred at −10° C. under nitrogen wasadded dropwise over 30 minutes triethylphosphonoacetate (112 g, 0.5mol). A further portion of sodium hydride (60% dispersion in oil, 20 g,0.5 mol) and tetrahydrofuran (1 l) was added followed by dropwiseaddition of triethylphosphonoacetate (112 g, 0.5 mol) over 30 minutes.3-Nitroacetophenone (165 g, 1 mol) was added portionwise such that thetemperature was maintained below 10° C. The mixture was allowed to warmto room temperature and was stirred for 1 h. Water (2 l) was added, andthe mixture was extracted with diethyl ether (2×1 l). The combinedextracts were washed with water (1 l), dried (MgSO₄), filtered andconcentrated in vacuo. The residue was recrystallised from isopropanolto give a first crop of the title compound as a white solid (90 g, 38%).

[0795] mp 43-44° C.

[0796] NMR (CDCl₃) δ: 1.34 (t, 3H), 2.60 (s, 3H), 4.25 (q, 2H), 6.20 (s,1H), 7.56 (t, 1H), 7.80 (d, 1H), 8.22 (d, 1H), 8.33 (s, 1H)

[0797] MS (thermospray): M/Z [MNH₄ ⁺] 253.1; C₁₂H₁₃NO₄+NH₄ requires253.1

[0798] Preparation 2

(E)-3-(3-Nitrophenyl-2-buten-1-ol

[0799] To a solution of ethyl (E)-3-(3-nitrophenyl)-2-butenoate(Preparation 1, 102 g, 0.43 mol) in toluene (1400 ml) at −10° C. undernitrogen was added dropwise over 3 h diisobutylaluminium hydride (1.0 Min toluene, 1 l), then the mixture was stirred at 0° C. for 1 h. Water(400 ml) was carefully added, followed by sodium hydrogen carbonate (300g). The resulting slurry was vigorously stirred for 10 min, then ethylacetate (2 l) was added, and the mixture stirred for 1 h. The mixturewas dried (MgSO₄), filtered and concentrated in vacuo to give the titlecompound as a pale brown oil (81 g, 97%).

[0800] NMR (CDCl₃) δ: 2.11 (s, 3H), 4.41 (d, 2H), 6.08 (t, 1H), 7.48 (t,1H), 7.72 (d, 1H), 8.10 (d,1H), 8.25 (s, 1H).

[0801] MS (thermospray): M/Z [MH⁺] 194.1; C₁₀H₁₁NO₃+H requires 194.1

[0802] Preparation 3

1-[(E)-3-Chloro-1-methyl-1-propenyl]-3-nitrobenzene

[0803] To a solution of N-chlorosuccinimide (52.3 g, 0.39 mol) indichloromethane (800 ml) at 0° C. was added dropwise over 1 hdimethylsulfide (27.9 ml, 0.38 mol). To the mixture was added dropwiseover 30 min at 0° C. a solution of (E)-3-(3-nitrophenyl)-2-buten-1-ol(Preparation 2, 72 g, 0.373 mol) in dichloromethane (200 ml). Themixture was warmed to room temperature over 1 h, then poured onto brine(500 ml). The layers were separated, and the aqueous layer extractedwith ether (500 ml). The organic extracts were combined, dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified by silicacolumn chromatography, eluting with 10:1 hexane/ethyl acetate, then as agradient up to 4:1 hexane/ethyl acetate. Appropriate fractions werecombined and concentrated in vacuo to give the title compound as a verypale yellow solid (69 g, 88%).

[0804] mp 46-47° C.

[0805] NMR (CDCl₃) δ: 2.20 (s, 3H), 4.27 (d, 2H) 6.10 (t, 1H), 7.52 (t,1H), 7.73 (d, 1H), 8.13 (d, 1H), 8.26 (s, 1H).

[0806] Preparation 4

1-[(E)-3-Bromo-1-methyl-1-propenyl]-3-nitrobenzene

[0807] To a solution of triphenylphosphine (5.15 g, 19.7 mmol) inacetonitrile (140 ml) was added dropwise over 5 minutes a solution ofbromine (3.15 g, 19.7 mmol) in acetonitrile (5 ml) at a rate such thatthe temperature did not exceed −10° C. The mixture was allowed to warmto room temperature, then to this was added a solution of(E)-3-(3-nitrophenyl)-2-buten-1-ol (Preparation 2, 4 g, 20.7 mmol) inacetonitrile (5 ml), The mixture was warmed gently to 65° C. for 1 h,cooled to room temperature and then poured onto diethyl ether (50 ml).The mixture was concentrated in vacuo, then diethyl ether (200 ml) wasadded. The mixture was filtered, concentrated again in vacuo and theresidue purified by silica column (300 g) chromatography, eluting with3:1 hexane/dichloromethane then 1:1 hexane/dichloromethane. Appropriatefractions were combined and concentrated in vacuo to give the titlecompound as a very pale yellow oil (4 g, 75%).

[0808] NMR (CDCl₃) δ: 2.20 (s, 3H), 4.20 (d, 2H) 6.20 (t, 1H), 7.51 (t,1H), 7.73 (d, 1H), 8.13 (d, 1H), 8.26 (s, 1H).

[0809] Preparation 5

Ethyl 3-(chloromethyl)-2-methyl-2-(3-nitrophenyl)cyclopropanecarboxylate

[0810] To a solution of1-[(E)-3-chloro-1-methyl-1-propenyl]-3-nitrobenzene (Preparation 3, 36g, 0.17 mol) in dichloromethane (50 ml) was added rhodium (II) acetatedimer (1 g, 2.3 mmol). To the mixture was added dropwise at roomtemperature over 8 h a solution of ethyl diazoacetate (50 ml, 54.25 g,0.475 mol) in dichloromethane (50 ml), then the mixture was stirred atroom temperature for 16 h. To the mixture was added dropwise at roomtemperature over 7 h a further solution of ethyl diazoacetate (50 ml,54.25 g, 0.475 mol) in dichloromethane (50 ml), then the mixture wasstirred at room temperature for a further 16 h. The mixture wasconcentrated in vacuo and the residue purified by silica column (1 kg)chromatography, eluting with 1:1 hexane/dichloromethane thendichloromethane. Product-containing fractions were combined andconcentrated in vacuo, then concentrated under a stream of nitrogen for16 h. The residue was purified further by silica column (2 kg)chromatography, eluting with 1:1 hexane/dichloromethane thendichloromethane. Product containing fractions were combined andconcentrated in vacuo, to give the title compound as a very pale yellowoil (14.2 g, 29%).

[0811] NMR (CDCl₃) δ: 1.34 (t, 3H), 1.60 (s, 3H), 2.01 (m, 1H), 2.20 (d,1H), 4.03 (dd, 1H), 4.15-4.27 (m, 3H), 7.50 (t, 1H), 7.69 (d, 1H), 8.10(d, 1H), 8.19 (s, 1H)

[0812] Preparation 6

Ethyl 3-(bromomethyl)-2-methyl-2-(3-nitrophenyl)cyclopropane Carboxylate

[0813] To a solution of1-[(E)-3-bromo-1-methyl-1-propenyl]-3-nitrobenzene (Preparation 4, 4 g,15.6 mmol) in dichloromethane (5 ml) was added rhodium (II) acetatedimer (100 mg, 0.22 mmol). To the mixture was added dropwise at roomtemperature over 4.5 h a solution of ethyl diazoacetate (3.1 ml, 2.84 g,25 mmol) in dichloromethane (15 ml). The mixture was filtered,concentrated in vacuo, and the residue purified by silica column (100 g)chromatography, eluting with 2:1 hexane/dichloromethane thendichloromethane. Product-containing fractions were combined andconcentrated in vacuo, then purified further by preparative HPLC(Condition 1). Combination and evaporation of appropriate fractions gavethe title compound as a colourless oil (0.5 g, 11%).

[0814] NMR (CDCl₃) δ: 1.34 (t, 3H), 1.60 (s, 3H), 2.10 (m, 1H), 2.22 (d,1H), 3.88 (dd, 1H), 4.06 (t, 1H), 4.23 (m, 2H), 7.50 (t, 1H), 7.72 (d,1H), 8.12 (d, 1H), 8.22 (s, 1H).

[0815] Preparation 7

6-Methyl-6-(3-nitrophenyl)-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hexan-2-one

[0816] To a solution of ethyl3-(chloromethyl)-2-methyl-2-(3-nitrophenyl)-cyclopropane carboxylate(Preparation 5, 14.4 g, 48.6 mmol), in N,N-dimethylformamide (120 ml)was added sodium hydrogen carbonate (12 g, 143 mmol) and3-phenylpropylamine (38.8 g, 41 ml, 290 mmol). The mixture was heated to150° C. for 7 h, then cooled to room temperature and poured onto water(1000 ml). The mixture was extracted with diethyl ether (2×500 ml), andthe combined extracts-were washed with water (2×250 ml), dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by silica(1000 g) column chromatography eluting with dichloromethane thendichloromethane/ethyl acetate 4:1. Product-containing fractions werecombined and concentrated in vacuo to give the title compound as a verypale yellow oil (6.2 g, 36%).

[0817] NMR (CDCl₃) δ: 1.37 (s, 3H), 1.88 (p, 2H), 2.16 (t, 1H), 2.36(d,1H), 2.66 (t, 2H), 3.23 (m, 1H), 3.38 (m, 2H), 3.70 (m, 1H), 7.20 (m,3H), 7.27 (m, 2H), 7.48 (t, 1H), 7.64 (d, 1H), 8.07 (d, 1H), 8.16 (s,1H)

[0818] MS (thermospray): M/Z [MH⁺] 351.1; C₂₁H₂₂N₂O₃+H requires 351.2

[0819] Preparation 8

3-[6-Methyl-3-(3-phenylpropyl)-3-azabicyclo3.1.0]hex-6-yl]phenylamine

[0820] Method A: To a solution of6-methyl-6-(3-nitrophenyl)-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hexan-2-one(Preparation 7, 6.2 g, 17.71 mmol) in anhydrous tetrahydrofuran (200 ml)at room temperature under nitrogen, was added dropwise a solution oflithium aluminium hydride (1.0M in tetrahydrofuran, 100 ml, 100 mmol),then the mixture was gently refluxed for 4 h. The mixture was cooled,then quenched by the careful addition of water (200 ml). The pH of themixture was adjusted to 4 by the addition of dilute hydrochloric acid,then adjusted to pH 10 by the addition of dilute sodium hydroxidesolution. The mixture was extracted with ethyl acetate (2×200 ml), andthe combined extracts were washed with water (100 ml), dried (Na₂SO₄),filtered and concentrated in vacuo to give 5.2 g of a yellow oil. Thiswas dissolved in ethanol (200 ml), Raney nickel (300 mg) was added andthe mixture was placed under an atmosphere of hydrogen (2 atm, 203 kPa)and stirred at 60° C. for 18 h. The mixture was cooled, filtered throughArbocel™, and concentrated in vacuo to give the title compound as a verypale yellow oil (4.6 g, 85%).

[0821] Or Method B:

[0822] (i) To a stirred solution of6-methyl-6-(3-nitrophenyl)-3-(3-phenylpropyl)azabicyclo[3.1.0]hexane-2,4-dione(Preparation 136, 15.0 g, 41.2 mmol) in tetrahydrofuran (60 ml) undernitrogen was added sodium borohydride (3.27 g, 86.4 mmol) and thereaction mixture was stirred at room temperature for 1 h. The reactionmixture was cooled to between 0° C. and 5° C. and borontrifluoridediethyletherate (16.36 g, 115 mmol) was added. The reaction mixture wasallowed to warm to room temperature over 2 h before being heated underreflux for a further 2 h. The reaction mixture was cooled to between 0°C. and 5° C. and an aqueous solution of piperazine (20.92 g in 120 ml)was added. The reaction mixture was then heated under reflux for 18 h.The tetrahydrofuran was removed by distillation and the reaction mixturewas allowed to cool to 50° C. Ethyl acetate (90 ml) was added and theresulting biphasic mixture was allowed to cool to room temperature. Thephases were separated and the organic extract was washed water (3×60 ml)to afford a solution of6-(3-nitrophenyl)-6-methyl-3-(3-phenylpropyl)azabicyclo[3.1.0]hexane inethyl acetate.

[0823] (ii) To the reaction mixture was added 5% palladium on charcoal(Johnsson Matthey type 87, 1.5 g) and the reaction mixture was placedunder an atmosphere of hydrogen (60 psi) at 25° C. for 16 h. Thecatalyst was removed by filtration through Celite™ and the filtrate wasconcentrated in vacuo to afford the title compound as a yellow oil whichcrystallised on standing (11.09 g, 88%).

[0824] NMR (CDCl₃, selected data for the free base): 1.52 (s, 3H),1.71-1.78 (m, 4H), 2.47 (t, 2H), 2.66 (t, 2H), 2.79 (d, 2H), 2.99 (d,2H), 3.59 (s, 2H), 6.49 (d, 1H), 6.60 (s, 1H), 6.65 (d, 1H), 7.06 (t,1H), 7.15-7.20 (m, 2H), 7.20-7.30 (m, 3H).

[0825] MS (APCI): M/Z [MH⁺] 307.3; C₂₁H₂₆N₂+H requires 307.2

[0826] Preparation 9

3-(3-Cyclohexylpropyl)-6-methyl6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexan-2-one

[0827] A solution of ethyl3-(chloromethyl)-2-methyl-2-(3-nitrophenyl)cyclopropane carboxylate(Preparation 5, 1 g, 3.36 mmol) in 3-cyclohexylpropylamine([Preparation—Eur. J. Med. Chem. (1992), 27, 321-330], 2.9 g, 20.5 mmol)was heated to 160° C. for 16 h. The mixture was cooled, 2N hydrochloricacid solution (20 ml) was added and the mixture was extracted withdichloromethane (3×20 ml). The combined extracts were dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by silica(200 g) column chromatography eluting with dichloromethane then diethylether. Appropriate fractions were combined and concentrated in vacuo togive the title compound as an amber oil (870 mg, 73%).

[0828] NMR (CDCl₃) δ: 0.90 (m, 2H), 1.22 (m, 6H), 1.38 (s, 3H),1.47-1.60 (m, 2H), 1.60-1.75 (m, 5H), 2.14 (t, 1H), 2.37 (d, 1H),3.08-3.30 (m, 2H), 3.36 (d, 1H), 3.73 (dd, 1H), 7.48 (t, 1H), 7.64 (d,1H), 8.08 (d, 1H), 8.16 (s, 1H)

[0829] MS (thermospray): M/Z [MH⁺] 357.1; C₂₁H₂₈N₂O₃+H requires 357.2

[0830] Preparation 10

3-[3-(3-Cyclohexylpropyl)-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]aniline

[0831] To a solution of3-(3-cyclohexylpropyl)-6-methyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexan-2-one(Preparation 9, 56 mg, 0.16 mmol) in anhydrous tetrahydrofuran (2.5 ml)at room temperature under nitrogen was added dropwise a solution oflithium aluminium hydride (1.0M in tetrahydrofuran, 0.8 ml, 0.8 mmol),then the mixture was gently refluxed for 4.5 h. The mixture was cooled,then quenched by the careful addition of water (30 ml). The pH of themixture was adjusted to 1 by the addition of dilute hydrochloric acid,then adjusted to pH 10 by the addition of dilute sodium hydroxidesolution. The mixture was extracted with ethyl acetate (40 ml) and theorganic extract was washed with water (10 ml), dried (Na₂SO₄), filteredand concentrated in vacuo to give 50 mg of a yellow oil. This wasdissolved in ethanol (6 ml), and Raney nickel (50 mg) was added and themixture was placed under an atmosphere of hydrogen (2 atm, 203 kPa) andstirred at 60° C. for 7 h. The mixture was cooled, filtered throughArbocel™, and concentrated in vacuo, to give the title compound as avery pale yellow oil (50 mg, 99%).

[0832] NMR (CDCl₃) δ: 0.90 (m, 2H), 1.06-1.31 (m, 6H), 1.43 (s, 3H),1.58-1.76 (m, 7H), 2.02 (s, 2H), 2.70 (t, 2H), 2.97 (d, 2H), 3.42 (m,2H), 6.40-6.63 (m, 3H), 7.08 (m,1H)

[0833] MS (thermospray): M/Z [MH⁺] 313.4; C₂₁H₃₂N₂+H requires 313.3

[0834] Preparation 11

3-Hexyl-6-methyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0hexan-2-one

[0835] To a solution of ethyl3-(chloromethyl)-2-methyl-2-(3-nitrophenyl)cyclopropane carboxylate(Preparation 5, 20 g, 67.2 mmol) in hexylamine (36 ml, 270 mmol) wasadded sodium hydrogen carbonate (5.64 g, 67.2 mmol), and the mixture washeated at 100° C. for 16 h. The mixture was cooled, diluted with water(80 ml) and extracted with dichloromethane (3×150 ml). The combinedextracts were dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was purified by silica column chromatography, eluting with agradient of 2:1 to 1:2 hexane/ethyl acetate. Appropriate fractions werecombined and concentrated in vacuo to give the title compound as a verypale yellow oil (14.2 g, 67%).

[0836] NMR (CDCl₃) δ: 0.90 (t, 3H), 1.23-1.38 (m, 6H), 1.38 (s, 3H),1.46-1.60 (m, 2H), 2.17 (t, 1H), 2.37 (d, 1H), 3.11-3.40 (m, 3H), 3.71(dd, 1H), 7.49 (t, 1H), 7.65 (m,1H), 8.08 (d, 1H), 8.15 (s, 1H)

[0837] MS (APCI): M/Z [MH⁺] 317.5; C₁₈H₂₄N₂O₃+H requires 317.2

[0838] Preparation 12

3-(3-Hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine

[0839] To a solution of3-hexyl-6-methyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexan-2-one(Preparation 11, 10.7 g, 33.86 mmol) in tetrahydrofuran (500 ml) undernitrogen, was added dropwise over 1 h at room temperature a 1.0 Msolution of lithium aluminium hydride in tetrahydrofuran (100 ml, 100mmol). The mixture was heated to 50° C. for 2 h, then cooled to roomtemperature. Water (50 ml) was carefully added, and the mixture wasstirred for 1 h, before the tetrahydrofuran was removed in vacuo. Theaqueous residue was acidified by the addition of 2N hydrochloric acid(20 ml) and then basified with the addition of 2N sodium hydroxidesolution (25 ml). The mixture was extracted with ethyl acetate (3×250ml). The combined extracts were dried (MgSO₄), filtered and concentratedin vacuo. The residue was dissolved in ethanol (450 ml), Raney nickel(500 mg) was added, and the mixture was placed under an atmosphere ofhydrogen (2 atm, 203 kPa) and stirred at 50° C. for 24 hours. Themixture was filtered through Celite™, and concentrated in vacuo. Theresidue was purified by silica column chromatography, eluting with80:20:2 ethyl acetate/methanol/ammonia solution (0.880).Product-containing fractions were combined and concentrated in vacuo togive the title compound as a colourless oil (3.3 g, 36%).

[0840] NMR (CDCl₃) δ: 0.90 (t, 3H), 1.30 (m, 6H), 1.42 (m, 2H), 1.46 (s,3H), 1.74 (s, 2H), 2.43 (t, 2H), 2.82 (d, 2H), 2.93 (d, 2H), 6.48 (d,1H), 6.59 (s, 1H), 6.65 (d, 1H), 7.05 (t, 1H)

[0841] MS (thermospray): M/Z [MH⁺] 273.4; C₁₈H₂₈N₂+H requires 273.2

[0842] Preparation 13

Ethyl (E)-3-(3-nitrophenyl)-2-pentenoate

[0843] To a solution of sodium hydride (60% dispersion in oil, 40 g, 1.0mol) in tetrahydrofuran (2 l) stirred at −10° C. under nitrogen wasadded dropwise over 30 minutes triethylphosphonoacetate (224 g, 1.0mol). 3-Nitropropiophenone (180 g, 1 mol) was added portionwise suchthat the temperature was maintained below 10° C. The mixture was allowedto warm to room temperature and was stirred for 18 h. Water (1.5 l) wasadded, and the mixture was extracted with diethyl ether (2×1 l). Thecombined extracts were washed with water (1 l), dried (MgSO₄), filteredand concentrated in vacuo and the residue was purified by silica column(4×2 kg) chromatography eluting with 12:1 hexane/diethyl ether.Appropriate fractions were combined and concentrated in vacuo to givethe title compound as a very pale yellow oil (105 g, 42%).

[0844] NMR (CDCl₃) δ: 1.08 (t, 3H), 1.33 (t, 3H), 3.13 (q, 2H), 4.22 (q,2H),6.05 (s, 1H), 7.56 (t, 1H), 7.76 (d, 1H), 8.21 (d, 1H), 8.30 (s, 1H)

[0845] MS (thermospray): m/z [MH⁺] 250.0; C₁₃H₁₅NO₄+H requires 250.1

[0846] Preparation 14

(E)-3-(3-Nitrophenyl)-2-penten-1-ol

[0847] To a solution of ethyl (E)-3-(3-nitrophenyl)-2-pentenoate(Preparation 13, 105 g, 0.43 mol) in toluene (1400 ml) at −10° C. undernitrogen was added dropwise over 3 h diisobutylaluminium hydride (1.0 Min toluene, 1 l, 1.0 mol), then the mixture was stirred at 0° C. for 1hour. Water (400 ml) was carefully added, followed by sodium hydrogencarbonate (700 g). The resulting slurry was vigorously stirred for 10minutes, then ethyl acetate (2 l) was added, and the mixture stirred for1 h. The mixture was dried (MgSO₄), filtered and concentrated in vacuoto give the title compound as a pale brown oil (80 g, 90%).

[0848] NMR (CDCl₃) δ: 0.99 (t, 3H), 2.60 (q, 2H), 4.39 (d, 2H), 5.91 (t,1H), 7.47 (t, 1H), 7.67 (d, 1H), 8.09 (d, 1H), 8.20 (s, 1H)

[0849] Preparation 15

1-[(E)-3-Chloro-1-ethyl-1-propenyl]-3-nitrobenzene

[0850] To a solution of N-chlorosuccinimide (52.3 g, 0.39 mol) indichlorometae (1.2 l) at 0° C. was added dropwise over 20 minutesdimethylsulfide (27.9 ml, 0.38 mol). To the mixture was added dropwiseover 20 minutes at 0° C. a solution of(E)-3-3-nitrophenyl)-2-penten-1-ol (Preparation 14, 80 g, 0.39 mol) indichloromethane (300 ml). The mixture was warmed to room temperatureover 1 h, stirred at room temperature for 16 h, then partitioned betweenwater (2 l) and dichloromethane (1 l). The layers were separated and theorganic layer was dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was purified by silica column chromatography (2 kg), elutingwith 10:1 hexane/diethyl ether. Appropriate fractions were combined andconcentrated in vacuo to give the title compound as a very pale yellowoil (54 g, 62%).

[0851] NMR (CDCl₃) δ: 1.33 (t, 3H), 2.63 (q, 2H), 4.27 (d, 2H), 5.94 (t,1H), 7.52 (t, 1H), 7.69 (d, 1H), 8.15 (d, 1H), 8.23 (s, 1H).

[0852] Preparation 16

Ethyl 3-(chloromethyl)-2-ethyl-2-(3-nitrophenyl)cyclopropanecarboxylate

[0853] To a solution of1-[(E)-3-chloro-1-ethyl-1-propenyl]-3-nitrobenzene (Preparation 15, 50g, 0.22 mol) in dichloromethane (40 ml) was added rhodium (II) acetatedimer (2.0 g, 4.6 mmol). To the mixture was added dropwise at roomtemperature over 6 hours a solution of ethyl diazoacetate (50 ml, 54.25g, 0.475 mol) in dichloromethane (50 ml), then the mixture stirred atroom temperature for 16 hours. To the mixture was added dropwise at roomtemperature over 7 hours a solution of ethyl diazoacetate (20 ml, 21.70g 0.190 mol) in dichloromethane (20 ml), then the mixture was stirred atroom temperature for 16 h. The mixture was concentrated in vacuo and theresidue purified by silica column (1 kg) chromatography, eluting with1:1 hexane/dichloromethane. Product-containing fractions were combinedand concentrated in vacuo to give the title compound as a pale orangeoil (10.5 g, 15%).

[0854] NMR (CDCl₃) δ: 0.79 (t, 3H), 1.33 (t, 3H), 1.93-2.11 (m, 3H),2.20 (d, 1H), 4.04 (dd, 1H), 4.23 (m, 3H), 7.51 (t, 1H), 7.68 (d, 1H),8.13 (d, 1H), 8.17 (s, 1H)

[0855] Preparation 17

6-Ethyl-6-(3-nitrophenyl)-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hexan-2-one

[0856] To a solution of ethyl3-(chloromethyl)-2-ethyl-2-(3-nitrophenyl)cyclopropane carboxylate(Preparation 16, 3.5 g, 11.2 mmol), in N,N-dimethylformamide (33 ml) wasadded sodium hydrogen carbonate (3.3 g, 39 mmol) and 3-phenylpropylamine(10.6 g, 11.2 ml, 79.2 mmol). The mixture was heated to 150° C. for 12h, then cooled to room temperature and partitioned between water (500ml) and diethyl ether (500 ml). The organic layer was washedsuccessively with water (4×250 ml). The aqueous layers were combined andextracted with diethyl ether (250 ml). The combined organic extractswere dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by silica (200 g) column chromatography eluting withdichloromethane. Product-containing fractions were combined andconcentrated in vacuo to give the title compound as a very pale yellowoil (1.8 g, 43%).

[0857] NMR (CDCl₃) δ: 0.87 (t, 3H), 1.64 (m, 2H), 1.86 (m, 2H), 2.15 (t,1H), 2.37 (d, 1H), 2.65 (t, 2H), 3.26 (m, 1H), 3.37 (m, 2H), 3.67 (dd,1H), 7.20 (m, 3H), 7.27 (m, 2H), 7.48 (t, 1H), 7.67 (d, 1H), 8.08 (d,1H), 8.17 (s, 1H)

[0858] Preparation 18

3-[6-Ethyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine

[0859] To a solution of6-ethyl-6-(3-nitrophenyl)-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hexan-2-one(Preparation 17, 1.8 g, 4.9 mmol) in anhydrous tetrahydrofuran (60 ml)at room temperature under nitrogen, was added dropwise a solution oflithium aluminium hydride (1.0M in tetrahydrofuran, 32 ml, 32 mmol) andthe mixture was gently refluxed for 6 h. The mixture was cooled, thenquenched by carefully pouring into ice cold hydrochloric acid (1N, 400ml). The acidic layer was extracted with diethyl ether (300 ml). The pHof the aqueous layer was adjusted to 10 by the addition of potassiumcarbonate and extracted with diethyl ether (300 ml). The organic layerswere combined, dried (MgSO₄), filtered and concentrated in vacuo to givea yellow oil (1.2 g). This was dissolved in ethanol (60 ml), Raneynickel (120 mg) was added and the mixture was placed under an atmosphereof hydrogen (2 atm, 203 kPa) and stirred at 60° C. for 40 h. The mixturewas cooled, filtered through Arbocel™, and concentrated in vacuo to givethe title compound as a very pale yellow oil (1.3 g, 82%).

[0860] NMR (CDCl₃) δ: 0.86 (m, 3H), 1.88 (m, 6H), 2.64 (m, 4H), 2.96 (m,2H), 3.09 (m, 2H), 6.46-6.75 (m, 4H), 7.06 (m, 1H), 7.13-7.35 (m, 4H)

[0861] MS (electrospray): m/z [MH⁺] 321.1; C₂₂H₂₈N₂+H requires 321.2

[0862] Preparation 19

6Ethyl-3-hexyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexan-2-one

[0863] To a solution of ethyl3-(chloromethyl)-2-ethyl-2-(3-nitrophenyl)cyclopropane carboxylate(Preparation 16, 4.0 g, 12.8 mmol), was added sodium hydrogen carbonate(1.3 g, 15.4 mmol) and hexylamine (15.3 g, 20 ml, 151 mmol). The mixturewas heated to 150° C. for 12 h, then cooled to room temperature andpartitioned between hydrochloric acid (2N, 500 ml) and ethyl acetate(2×500 ml). The combined organic layers were washed with water (500 ml),dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by silica (200 g) column chromatography eluting with a gradientof dichloromethane/ethyl acetate 100:0 to 90:10. Product-containingfractions were combined and concentrated in vacuo to give the titlecompound as an orange oil (1.4 g, 32%).

[0864] NMR (CDCl₃) δ: 0.93 (m, 6H), 1.30 (m, 6H), 1.52 (m, 2H), 1.62 (m,2H), 2.17 (m, 1H), 2.38 (d, 1H), 3.25 (m, 2H), 3.38 (d, 1H), 3.69 (dd,1H), 7.50 (t, 1H), 7.68 (d, 1H), 8.10 (d, 1H), 8.18 (s, 1H)

[0865] MS (electrospray): m/z [MH⁺] 331.1; C₁₉H₂₆N₂O₃+H requires 331.2

[0866] Preparation 20

3-(6-Ethyl-3-hexyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine

[0867] To a solution of6-ethyl-3-hexyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexan-2-one(Preparation 19, 1.4 g, 4.2 mmol) in anhydrous tetrahydrofuran (42 ml)at room temperature under nitrogen, was added dropwise a solution oflithium aluminium hydride (1.0 M in tetrahydrofuran, 23 ml, 23 mmol),then the mixture was gently heated under reflux for 18 h. The mixturewas cooled, then quenched by carefully pouring onto ice coldhydrochloric acid (1N, 400 ml). The acidic layer was extracted withdiethyl ether (2×200 ml). The pH of the aqueous layer was adjusted to 10by the addition of potassium carbonate and then was extracted withdiethyl ether (300 ml). The organic extract was dried (MgSO₄), filteredand concentrated in vacuo to give a yellow oil (1.2 g). This wasdissolved in ethanol (50 ml), Raney nickel (100 mg) was added, then themixture was placed under an atmosphere of hydrogen (2 atm, 203 kPa) andstirred at 60° C. for 40 h. The mixture was cooled, filtered throughArbocel™, and concentrated in vacuo to give the title compound as a verypale yellow oil (1.1 g, 77%).

[0868] NMR (CDCl₃) δ: 0.85 (m, 6H), 1.27 (m, 6H), 1.44 (m, 2H), 1.87 (m,4H), 2.48 (m, 2H), 2.93 (m, 4H), 6.46-6.73 (m, 3H), 7.04 (m, 1H)

[0869] MS (electrospray): m/z [MH⁺] 287.1; C₁₉H₃₀N₂+H requires 287.2

[0870] Preparation 21

(E)-3-(3-Nitorphenyl)-2-propen-1-ol

[0871] To a solution of ethyl (E)-3-(3-nitrophenyl)-2-propenoate (8.04g, 36 mmol) in dichloromethane at 0° C. under nitrogen was addeddropwise over 5 minutes diisobutylaluminium hydride (1.0 M solution indichloromethane, 80 ml, 80 mmol). The mixture was stirred at 0° C. for10 minutes, then allowed to warm to room temperature over 30 minutes.Hydrochloric acid (1N, 500 ml) was added, the layers were separated andthe aqueous layer was extracted with dichloromethane (2×250 ml). Theorganic layers were combined, washed with brine (2×100 ml), filtered andconcentrated in vacuo to give the title compound as a red oil.

[0872] NMR (CDCl₃) δ: 4.40 (d, 2H), 6.50 (dt, 1H), 6.70 (d, 1H), 7.48(t, 1H), 7.67 (d, 1H), 8.09 (d, 1H), 8.23 (s,1H).

[0873] Preparation 22

1-[(E)-3-Bromo-1-propenyl]-3-nitrobenzene

[0874] To a solution of triphenylphosphine (1.47 g, 5.6 mmol) inacetonitrile (35 ml) at 0° C. was added dropwise over 5 minutes asolution of bromine (0.88 g, 5.6 mmol) in acetonitrile (5 ml) at a ratesuch that the temperature was kept between 5° C. and 10° C. The mixturewas then allowed to warm to room temperature, then to this was addeddropwise a solution of (E)-3-(3-nitrophenyl)-2-propen-1-ol (Preparation21, 1 g, 5.6 mmol) in acetonitrile (5 ml). The mixture was warmed to 65°C. for 40 min, cooled to room temperature, and poured onto diethyl ether(150 ml). The mixture was concentrated in vacuo. The residue waspurified by silica (10 g) column chromatography eluting with hexane thendichloromethane. Product-containing fractions were combined andconcentrated in vacuo, and the residue recrystallised from cyclohexaneto give the title compound as a very pale yellow solid (0.82 g, 61%).

[0875] NMR (CDCl₃) δ: 4.18 (d, 2H), 6.48-6.60 (m, 1H), 6.72 (d, 1H),7.52 (t, 1H), 7.68 (d, 1H), 8.12 (d, 1H), 8.24 (s,1H).

[0876] Preparation 23

Ethyl 2-(bromomethyl)-3-(3-nitrophenyl)cyclopropane Carboxylate

[0877] To a solution of 1-[(E)-3-bromo-1-propenyl]-3-nitrobenzene(Preparation 22, 820 mg, 3.23 mmol) in dichloromethane (3 ml) was addedrhodium (II) acetate dimer (20 mg, 0.046 mmol). To the mixture was addeddropwise at room temperature over 3 h a solution of ethyl diazoacetate(0.47 ml, 510 mg, 4.47 mmol) in dichloromethane (3 ml), then the mixturewas stirred at room temperature for 66 h. The mixture was purified bysilica (100 g) column chromatography eluting with hexane:dichloromethane100:0 to 50:50. Product containing fractions were combined andconcentrated in vacuo to afford the title compound as a colourless oil(65 mg, 7%).

[0878] NMR (CDCl₃) δ: 1.33 (t, 3H), 2.20 (m, 1H), 2.35 (m, 1H), 2.80 (m,1H), 3.74 (t, 1H), 3.90 (m, 1H), 4.25 (m, 2H), 7.58 (m, 2H), 7.98 (s,1H), 8.09 (m, 1H)

[0879] Preparation 24

6-(3-Nitrophenyl)-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hexan-2-one

[0880] To a solution of ethyl2-(bromomethyl)-3-(3-nitrophenyl)cyclopropane carboxylate (Preparation23, 60 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) was added sodiumhydrogen carbonate (30 mg, 0.36 mmol) and 3-phenylpropylamine (30 mg, 31μl, 0.22 mmol). The mixture was heated to 150° C. for 1 hour, thencooled to room temperature and stirred for 16 hours. Water (30 ml) wasadded and the mixture was extracted with diethyl ether (2×50 ml). Thecombined extracts were concentrated in vacuo and the residue waspurified by silica (5 g) column chromatography eluting withdichloromethane then 4:1 dichloromethane:ethyl acetate.Product-containing fractions were combined and concentrated in vacuo togive the title compound as a colourless glassy solid (55 mg, 90%).

[0881] NMR (CDCl₃) δ: 1.85 (m, 2H), 2.02 (m, 1H), 2.20 (m, 1H), 2.32(m,1H), 2.64 (t, 2H), 3.20-3.40 (m, 2H), 3.49 (d, 1H), 3.65 (dd, 1H),7.14-7.49 (m , 7H), 7.87 (s, 1H), 8.05 (d, 1H)

[0882] MS (APCI): m/z [MH⁺] 337.2; C₂₀H₂₀N₂O₃+H requires 337.2

[0883] Preparation 25

3-[3-(3-Phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenyl Amine

[0884] To a solution of6-(3-nitrophenyl)-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hexan-2-one(Preparation 24, 55 mg, 0.16 mmol) in tetrahydrofuran (3 ml) undernitrogen, was added dropwise at room temperature a 1.0 M solution oflithium aluminium hydride in tetrahydrofuran (0.81 ml, 0.81 mmol). Themixture was heated to 60° C. for 4 h. Further lithium aluminium hydridein tetrahydrofuran (1.0M, 0.3 ml, 0.3 mmol) was added, and the mixturewas heated at 60° C. for 20 minutes, then cooled to room temperature.Water (30 ml) was carefully added, then the residue was acidified by theaddition of 2N hydrochloric acid (5 ml), and then basified with 2Nsodium hydroxide solution (6 ml). The mixture was extracted with ethylacetate (3×50 ml). The combined extracts were dried (Na₂SO₄), filteredand concentrated in vacuo. The residue was dissolved in ethanol (5 ml),Raney nickel (50 mg) was added, and the mixture was placed under anatmosphere of hydrogen (2 atm, 203 kPa) and stirred at 60° C. for 16 h.The mixture was filtered through Celite™ and concentrated in vacuo togive the title compound as a pale yellow oil (35 mg, 75%).

[0885] NMR (CDCl₃) δ: 1.74 (m, 2H), 1.95 (m, 2H), 2.39 (br.s, 1H), 2.65(m, 6H), 3.38 (br.d, 2H), 6.28-6.50 (m, 3H), 7.05 (m, 1H), 7.15-7.34 (m,5H).

[0886] MS (thermospray): M/Z [MH⁺] 293.3; C₂₀H₂₄N₂+H requires 293.2

[0887] Preparation 26

Ethyl 2-(bromomethyl)-3-phenylcyclopropanecarboxylate

[0888] To a solution of [(E)-3-bromo-1-propenyl]benzene (705 mg, 3.58mmol) in dichloromethane (1 ml) was added rhodium (II) acetate dimer (20mg, 0.05 mmol). To the mixture was added dropwise at room temperatureover 4 h a solution of ethyl diazoacetate (0.43 ml, 0.47 g, 4.15 mmol)in dichloromethane (2.5 ml). The mixture was stirred at room temperaturefor 60 h. The mixture was purified by silica column (40 g)chromatography eluting with 1:1 hexane:dichloromethane thendichloromethane. Product-containing fractions were purified further bysilica column (10 g) chromatography eluting with 9:1hexane:dichloromethane then dichloromethane. Product-containingfractions were combined and concentrated in vacuo to give the titlecompound as a colourless oil (75 mg, 8%).

[0889] NMR (CDCl₃) δ: 1.32 (t, 3H), 2.16 (m, 1H), 2.27 (dd, 1H), 2.70(t, 1H), 3.76 (t, 1H), 3.90 (dd, 1H), 4.23 (m, 2H), 7.12 (d, 2H),7.17-7.36 (m, 3H)

[0890] Preparation 27

3-Hexyl-6-phenyl-3-azabicyclo[3.1.0]hexan-2-one

[0891] To a solution of ethyl2-(bromomethyl)-3-phenylcyclopropanecarboxylate (Preparation 26, 65 mg,0.22 mmol) in N,N-dimethylformamide (2 ml) was added sodium hydrogencarbonate (30 mg, 0.36 mmol) and hexylamine (33 μl, 26 mg, 0.26 mmol),and the mixture was heated to 150° C. for 3 h. The mixture was cooled,water (30 ml) was added, and the mixture was extracted with diethylether (2×30 ml). The extracts were combined, dried (Na₂SO₄), filteredand concentrated in vacuo. The mixture was purified by silica column (5g) chromatography eluting with 4:1 dichloromethane:ethyl acetate.Product-containing fractions were combined and concentrated in vacuo togive the title compound as a colourless oil (45 mg, 76%).

[0892] NMR (CDCl₃) δ: 0.89 (t, 3H), 1.28 (m, 6H), 1.48 (m, 2H), 2.00 (m,1H), 2.12 (m, 1H), 2.22 (m, 1H), 3.08-3.31 (m, 2H), 3.47 (d, 1H), 3.63(m, 1H), 7.03 (d, 2H), 7.12-7.33 (m, 3H)

[0893] MS (APCI): M/Z [MH⁺] 258.1; C₁₇H₂₃NO+H requires 258.2

[0894] Preparation 28

3-Benzyl-6-methyl6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexan-2-one

[0895] A solution of ethyl3-(chloromethyl)-2-methyl-2-(3-nitrophenyl)cyclopropane carboxylate(Preparation 5, 10 g, 33.6 mmol) in benzylamine (21.6 g, 201.6 mmol) washeated to 160° C. for 16 h. The mixture was cooled, 2N hydrochloric acidwas added (200 ml), and the mixture was extracted with dichloromethane(3×250 ml). The combined extracts were dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by silica (600 g) columnchromatography eluting with dichloromethane, then a gradient ofdichloromethane:ethyl acetate ending with pure ethyl acetate.Appropriate fractions were combined and concentrated in vacuo to givethe title compound as an amber oil (6 g, 55%).

[0896] NMR (CDCl₃) δ: 1.27 (s, 3H), 2.13 (t, 1H), 2.42 (d, 1H), 3.25 (d,1H), 3.62 (dd, 1H), 4.31 (d, 1H), 4.57 (d, 1H), 7.33 (m, 5H), 7.49 (t,1H), 7.63 (d, 1H), 8.08 (d, 1H), 8.13 (s, 1H)

[0897] MS (electrospray): M/Z [MH⁺] 323.1; C₁₉H₁₈N₂O₃+H requires 323.1

[0898] Preparation 29

6-(3-Aminophenyl)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-2-one

[0899] To a solution of3-benzyl-6-methyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexan-2-one(Preparation 28, 2 g, 6.2 mmol) in absolute ethanol (170 ml) was addedwater (30 ml), calcium chloride (344 mg, 3.1 mmol) and iron powder (3.02g, 53.8 mmol). The mixture was heated to reflux under nitrogen for 4 h,then cooled. The solution was filtered through silica (10 g) elutingwith methanol, then concentrated in vacuo to give the title compound asa white solid (1.73 g, 95%).

[0900] mp 150-151° C.

[0901] NMR (CDCl₃) δ: 1.22 (s, 3H), 2.03 (t, 1H), 2.33 (d, 1H), 3.15 (d,1H), 3.53 (dd, 1H), 4.23 (d, 1H), 4.54 (d, 1H), 6.53 (d, 1H), 6.66 (m,2H), 7.05 (t, 1H), 7.30 (m, 5H)

[0902] MS (electrospray): M/Z [MH⁺] 293.1; C₁₉H₂₀N₂O+H requires 293.2

[0903] Preparation 30

3-(3-Benzyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine

[0904] Lithium aluminium hydride (1M in tetrahydrofuran, 11.84 ml, 11.84mmol) was added dropwise to dry tetrahydrofuran (60 ml) under nitrogen.6-(3-Aminophenyl)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-2-one(Preparation 29, 1.73 g, 5.90 mmol) was suspended in dry tetrahydrofuran(100 ml) and added slowly to the lithium aluminium hydride solution bycannula. The reaction was then heated at 50° C. for 2 hours. Aftercooling, water (20 ml) was cautiously added to the solution, the pH ofthe aqueous layer was adjusted to 4 by the addition of 2N hydrochloricacid and then adjusted to 10 using dilute sodium hydroxide solution. Themixture was extracted with ethyl acetate (3×200 ml), and the combinedextracts were washed with water (100 ml), dried (Na₂SO₄) andconcentrated in vacuo to give the title compound as a yellow oil (1.58g, 96%).

[0905] NMR (CDCl₃) δ: 1.60 (s, 3H), 1.78 (s, 2H), 2.83 (d, 2H), 3.02 (d,2H), 3.67 (s, 2H), 6.48 (d, 1H), 6.60 (s, 1H), 6.67 (d, 1H), 7.05 (t,1H), 7.33 (m, 5H).

[0906] MS (electrospray): M/Z [MH⁺] 279.1; C₁₉H₂₂N₂+H requires 279.2

[0907] Preparation 31

Ethyl (E)-3-(3-cyanophenyl)-2-butenoate

[0908] To a solution of sodium hydride 60% dispersion in oil (8.28 g,0.19 mol) in tetrahydrofuran (300 ml) stirred at 0° C. under nitrogenwas added dropwise over 45 minutes triethyl phosphonoacetate (46.2 g,0.21 mol). The mixture was then stirred at room temperature for 30minutes. 3-Cyanoacetophenone (25.1 g, 0.172 mol) in tetrahydrofuran (200ml) was added via a cannula at room temperature and the brown reactionmixture was stirred for 1 h. Saturated ammonium chloride solution (150ml) was added, and the mixture was concentrated in vacuo. The aqueouslayer was extracted with ethyl acetate (3×150 ml). The combined extractswere dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by silica column chromatography eluting with a gradient ofhexane:ethyl acetate 100:0 to 70:30 to afford the title compound as amixture of the E and Z isomers (ratio 5:1) as a colourless oil whichsolidified on standing. This was taken on without further purification.

[0909] NMR (CDCl₃) for the E isomer δ: 1.34 (t, 3H), 2.58 (s, 3H), 4.25(q, 2H), 6.15 (s, 1H), 7.50 (t, 1H), 7.62-7.70 (m, 2H), 7.77 (s, 1H)

[0910] Preparation 32

(E)-3-(3-Cyanophenyl)-2-butenoic Acid

[0911] To a mixture of lithium hydroxide monohydrate (10.8 g, 0.26 mol)in tetrahydrofuran (100 ml) and water (100 ml) was added crude ethyl(E)-3-(3-cyanophenyl)-2-butenoate (Preparation 31) in tetrahydrofuran(150 ml). The resultant mixture was made homogeneous by the addition ofmethanol (approx. 50 ml), and then stirred at room temperature for 16 h.The mixture was concentrated in vacuo and acidified with 2N hydrochloricacid, following which a solid precipitated. The solid was collected bysuction filtration, washing with cold water. The solid was then driedand recrystallised from acetonitrile.

[0912] From the first crop, 15.8 g (49% over 2 steps) of the pureE-isomer was isolated.

[0913] NMR (CDCl₃) δ: 2.58 (s, 3H), 6.18 (s, 1H), 7.58 (t, 1H), 7.72 (d,1H), 7.81 (d, 1H), 7.90 (s, 1H)

[0914] Preparation 33

3-[(E)-3-Hydroxy-1-methyl-1-propenyl]benzonitrile

[0915] To a solution of (E)-3-(3-cyanophenyl)-2-butenoic acid(Preparation 32, 15.83 g, 84.6 mmol) and triethylamine (8.99 g, 88.8mmol) in tetrahydrofuran (150 ml) at 0° C. was added over 10 minutesethyl chloroformate (9.65 g, 88.8 mmol). The mixture was then stirred at0° C. for 30 minutes and at room temperature for a further 30 minutes.The resulting precipitate was collected by filtration and the solid waswashed with cold tetrahydrofuran (2×30 ml). The preformed mixedanhydride in tetrahydrofuran was then added over 30 minutes via cannulato sodium borohydride (11.2 g, 0.30 mol) in a mixture oftetrahydrofuran/water (4:1, 100 ml) at 0° C. The resultant mixture wasstirred at 0° C. for 1 h, at room temperature for 3 h and then cooled to0° C. 2N Hydrochloric acid was added cautiously until effervescence hadceased. The mixture was concentrated in vacuo and 1N hydrochloric acid(100 ml) was added. The aqueous solution was extracted with ethylacetate (3×150 ml) and the combined extracts were dried (MgSO₄),filtered and concentrated in vacuo. The crude oil was purified by silicacolumn chromatography eluting with a gradient of ethyl acetate:hexane(1:1 to 100:0). An impurity, unreacted starting carboxylic acid, wasremoved by a basic wash with 2N sodium hydroxide solution (150 ml) andthe pure product was extracted with dichloromethane (3×100 ml). Thecombined extracts were dried (MgSO₄), filtered and concentrated in vacuoto give the title compound as a colourless oil (11.9 g, 82%).

[0916] NMR (CDCl₃) δ: 1.4 (t, 1H), 2.05 (br. s, 3H), 4.40 (t, 2H), 6.01(m, 1H), 7.42 (t, 1H), 7.57 (d, 1H), 7.62 (d, 1H), 7.68 (s, 1H)

[0917] Preparation 34

3-[(E)-3-Chloro-1-methyl-1-propenyl]benzonitrile

[0918] To a solution of N-chlorosuccinimide (9.8 g, 73.1 mmol) indichloromethane (25 ml) at −10° C. was added dropwise over 15 minutesdimethylsulfide (5.4 ml, 73.1 mmol). The mixture was stirred at −10° C.for 30 min, then a solution of3-[(E)-3-hydroxy-1-methyl-1-propenyl]benzonitrile (from Preparation 33,11.9 g, 69.6 mmol) in dichloromethane (20 ml) was added dropwise over 15minutes at −10° C. The mixture was stirred at 0° C. for 1 h, and wasthen poured onto saturated brine (50 ml). The layers were separated, andthe aqueous layer was extracted with diethyl ether (2×50 ml). Theextracts were combined, washed with water (50 ml), dried (MgSO₄),filtered and concentrated in vacuo. The crude pale yellow oil (13.1 g,100%) was used directly in the next step.

[0919] NMR (CDCl₃) δ: 2.16 (s, 3H), 4.27 (d, 2H) 6.04 (t, 1H), 7.42 (t,1H), 7.59 (d, 1H), 7.63 (d, 1H), 7.68 (s, 1H)

[0920] Preparation 35

Ethyl 3-(chloromethyl)-2-(3-cyanophenyl)-2-methylcyclopropaneCarboxylate

[0921] To a solution of 3-[(E)-3-chloro-1-methyl-1-propenyl]benzonitrile(Preparation 34, 13.1 g, 69.6 mmol) in dichloromethane (20 ml) was addedrhodium (II) acetate dimer (0.46 g, 1.0 mmol). To the mixture was addeddropwise at room temperature over 8 h (via a syringe pump) a solution ofethyl diazoacetate (14.6 ml, 0.14 mol) in dichloromethane (20 ml). Thesolvent was removed in vacuo and the crude residue was then partiallypurified by silica column chromatography eluting withdichloromethane:hexane (80:20). This material was then dissolved indichloromethane (20 ml) containing rhodium (II) acetate dimer (0.46 g,1.0 mmol). To this mixture was added dropwise a solution of ethyldiazoacetate (14.6 ml, 0.14 mol) in dichloromethane (20 ml) at roomtemperature over 8 h. The mixture was concentrated in vacuo and theresidue purified by silica column chromatography eluting withhexane:dichloromethane (80:20) and then hexane:diethyl ether (80:20) togive the title compound as a colourless oil which solidified on standing(5.82 g, 30%).

[0922] NMR (CDCl₃) δ: 1.30 (t, 3H), 1.58 (s, 3H), 1.95 (m, 1H), 2.15 (m,1H), 4.00 (dd, 1H), 4.17-4.27 (m, 3H), 7.43 (t, 1H), 7.56 (d, 1H), 7.58(d, 1H), 7.62 (s, 1H)

[0923] Preparation 36

3-(3-Hexyl-6-methyl-2-oxo-3-azabicyclo[3.1.0]hex-6-yl)benzonitrile

[0924] To a solution of ethyl3-(chloromethyl)-2-(3-cyanophenyl)-2-methylcyclopropanecarboxylate(Preparation 35, 5.82 g, 21.1 mmol) in N,N-dimethylformamide (20 ml) atroom temperature was added sodium hydrogen carbonate (1.77 g, 21.1 mmol)followed by hexylamine (16.7 ml, 0.13 mol). The mixture was then heatedunder reflux for 16 h, cooled to room temperature and poured onto ice.After warming to room temperature, the mixture was partitioned againstdiethyl ether (50 ml). The two layers were separated and the aqueouslayer was extracted with diethyl ether (2×30 ml). The ethereal extractswere washed with water (50 ml), dried (MgSO₄), filtered and concentratedin vacuo. The crude oil was purified by silica column chromatographyeluting with a gradient of hexane:ethyl acetate (5:1 to 0:100) to affordthe title compound (2.2 g, 35%) as a colourless oil.

[0925] NMR (CDCl₃) δ: 0.82-0.91 (m, 3H), 1.20-1.40 (m, 9H), 1.47-1.58(m, 2H), 2.10 (m, 1H), 2.30 (m, 1H), 3.10-3.38 (m, 3H), 3.70 (dd, 1H),7.41 (t, 1H), 7.56 (m, 2H), 7.59 (s, 1H).

[0926] Preparation 37

3-[6-Methyl-2-oxo-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]-benzonitrile

[0927] To a solution of ethyl3-(chloromethyl)-2-3-cyanophenyl)-2-methylcyclopropanecarboxylate(Preparation 35, 170 mg, 0.62 mmol) in N,N-dimethylformamide (6.0 ml) atroom temperature was added sodium hydrogen carbonate (52 mg, 0.62 mmol)followed by 3-phenylpropylamine (0.35 ml, 2.47 mmol). The mixture washeated at 100° C. for 6 h and under reflux for 5 h. After the mixturehad cooled to room temperature, water (4 ml) was added and the aqueouslayer was extracted with diethyl ether (3×4 ml). The combined etherealextracts were dried (MgSO₄), filtered and concentrated in vacuo. Thecrude oil was purified by silica column chromatography eluting with agradient of hexane:ethyl acetate (50:50 to 0:100) to afford the titlecompound (80 mg, 40%) as a colourless oil.

[0928] NMR (CDCl₃) δ: 1.35 (s, 3H), 1.87 (m, 2H), 2.10 (t, 1H), 2.30 (d,1H), 2.64 (m, 2H), 3.16-3.40 (m, 3H), 3.70 (dd, 1H), 7.17-7.60 (m, 9H)

[0929] Preparation 38

6-Methyl-3-(3-phenylpropyl)-6-{3-[5-(trimethylsilyl)-1H-1,2,3-triazol-5-yl]phenyl}-3-azabicyclo[3.1.0]hexan-2-one

[0930] To a solution of (trimethylsilyl)diazomethane (0.36 ml, 0.74mmol) in tetrahydrofuran (4 ml) at 0° C. was added n-butyllithium (0.40ml, 0.64 mmol) dropwise over a few minutes. The mixture was then stirredat 0° C. for 30 minutes. To this mixture was added3-[6-methyl-2-oxo-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]benzonitrile(Preparation 37, 78.0 mg, 0.24 mmol) in tetrahydrofuran (2 ml) at 0° C.via a cannula. The mixture was then allowed to warm to room temperatureand stirred for 16 h. Further reaction was quenched by the addition ofsaturated ammonium chloride solution (5 ml) and the aqueous layer wasextracted with ethyl acetate (3×5 ml). The combined extracts were dried(MgSO₄), filtered and concentrated in vacuo. The crude oil was purifiedby silica column chromatography eluting with a gradient of hexane:ethylacetate (50:50 to 0:100) to afford the title compound (58 mg, 55%) as acolourless oil.

[0931] NMR (CDCl₃) δ: 0.37 (s, 9H), 1.38 (s, 3H), 1.85 (m, 2H), 2.09 (t,1H), 2.40 (d, 1H), 2.64 (m, 2H), 3.16-3.44 (m, 3H), 3.65 (dd, 1H),7.17-7.45 (m, 8H), 7.64 (s, 1H)

[0932] Preparation 39

3-Hexyl-6-methyl-6-{3-[5-(trimethylsilyl)-1H-1,2,3-triazol-5-yl]phenyl}-3-azabicyclo[3.1.0]hexan-2-one

[0933] To a solution of (trimethylsilyl)diazomethane (4.32 ml, 8.64mmol) in tetrahydrofuran (10 ml) at 0° C. was added n-butyllithium (3.46ml, 8.64 mmol) dropwise over 10 minutes. The mixture was then stirred at0° C. for 30 minutes. To this mixture was added3-(3-hexyl-6-methyl-2-oxo-3-azabicyclo[3.1.0]hex-6-yl)benzonitrile(Preparation 36, 852 mg, 2.88 mmol) in tetrahydrofuran (12 ml) at 0° C.via cannula. The mixture was then allowed to warm to room temperatureand stirred for 48 h. Further reaction was quenched by the addition ofsaturated ammonium chloride solution (25 ml), and the tetrahydrofuranwas removed in vacuo. The aqueous solution was extracted with ethylacetate (3×20 ml). The combined extracts were dried (MgSO₄), filteredand concentrated in vacuo. The crude oil was purified by silica columnchromatography, eluting with a gradient of hexane:ethyl acetate (66:33to 0:100) to afford the title compound (1.2 g, 100%) as a colourlessoil.

[0934] NMR (CDCl₃) δ: 0.38 (s, 9H), 0.82-0.95 (m, 3H), 1.30-1.40 (m,9H), 1.47-1.58 (m, 2H), 2.08 (t, 1H), 2.40 (d, 1H), 3.10-3.38 (m, 3H),3.67 (dd, 1H), 7.30-7.45 (m, 3H), 7.63 (s, 1H).

[0935] Preparation 40

3-Hexyl-6-methyl-6-[3-(1H-1,2,3-triazol-5-yl)phenyl]-3-azabicyclo[3.1.0]hexan-2-one

[0936] To a solution of3-hexyl-6-methyl-6-{3-[5-(trimethylsilyl)-1H-1,2,3-triazol-4-yl]phenyl}-3-azabicyclo[3.1.0]hexan-2-one(Preparation 39, 1.2 g, 2.88 mmol) in ethanol (15 ml) was addedpotassium fluoride (183 mg, 3.17 mmol) and a few drops of concentratedhydrochloric acid. The mixture was heated at reflux for 1.5 hours andthen cooled to room temperature. The solvent was removed in vacuo andthe crude residue was dissolved in dichloromethane (40 ml) and washedwith 10% potassium carbonate solution. The extract was dried (MgSO₄),filtered and concentrated in vacuo to give the crude product which wasused directly in the next step.

[0937] NMR (CDCl₃) δ: 0.80-0.98 (m, 3H), 1.25-1.40 (m, 9H), 1.43-1.58(m, 2H), 2.10 (t, 1H), 2.43 (d, 1H), 3.13-3.40 (m, 3H), 3.65-3.76 (m,1H), 7.25-7.38 (m, 2H) 7.63 (d, 1H), 7.86 (s, 1H), 7.99 (s, 1H)

[0938] Preparation 41

6-Methyl-3-(3-phenylpropyl)-6-[3-(1H-1,2,3-triazol-5-yl)phenyl]-3-azabicyclo[3.1.0]hexan-2-one

[0939] To a solution of6-methyl-3-(3-phenylpropyl)-6-{3-[5-(trimethylsilyl)-1H-1,2,3-triazol-4-yl]phenyl}-3-azabicyclo[3.1.0]hexan-2-one(Preparation 38, 58.0 mg, 0.13 mmol) in ethanol (2 ml) was addedpotassium fluoride (8.3 mg, 0.14 mmol) and a drop of concentratedsulphuric acid. The mixture was heated at reflux for 4 hours and thenstirred at room temperature for 16 hours. The solvent was removed invacuo and the crude residue was absorbed onto silica. This material wasthen purified by silica column chromatography eluting first withhexane:ethyl acetate (1:1) and then increasing gradually to neat ethylacetate. The desired title compound (32 mg, 66%) was isolated as acolourless oil.

[0940] NMR (CDCl₃) δ: 1.38 (s, 3H), 1.85 (p, 2H), 2.09 (t, 1H), 2.45 (d,1H), 2.65 (m, 2H), 3.19-3.48 (m, 3H), 3.70 (dd, 1H), 7.17-7.40 (m, 7H),7.66 (d, 1H), 7.86 (br. s, 1H), 7.99 (s, 1H)

[0941] MS (thermospray): m/z [MH⁺] 373.5; C₂₃H₂₄N₄O+H requires 373.2

[0942] Preparation 42

Ethyl 3-(3-hexyl-6-methyl-2-oxo-3-azabicyclo[3.1.0]hex-6-yl)benzeneCarboximidoate

[0943] Hydrogen chloride gas was bubbled through a solution of3-(3-hexyl-6-methyl-2-oxo-3-azabicyclo[3.1.0]hex-6-yl)benzonitrile(Preparation 36, 0.55 g, 1.86 mmol) in ethanol (8 ml) at 0° C. for 1 h.The reaction vessel was then sealed and left standing in the fridge for48 h. The mixture was allowed to warm to room temperature and thesolvent was removed in vacuo (to afford the title compound as itshydrochloride salt). The residue was dissolved in dichloromethane (20ml) and washed with 10% w/v potassium carbonate solution (2×10 ml). Theorganic layer was dried (MgSO₄), filtered and concentrated in vacuo. Thecrude title compound (700 mg) was isolated as a colourless oil which wastaken on without further purification.

[0944] NMR (CDCl₃) δ: 0.82-0.91 (m, 3H), 1.20-1.38 (m, 9H), 1.42 (t,3H), 1.44-1.58 (m, 2H), 2.10 (m, 1H), 2.35 (m, 1H), 3.10-3.38 (m, 3H),3.68 (dd, 1H), 4.38 (t, 2H), 7.30-7.44 (m, 2H), 7.60 (m, 1H), 7.68 (s,1H).

[0945] Preparation 43

3-Hexyl-6-methyl-6-[3-(4H-1,2,4-triazol-3-yl)phenyl]-3-azabicyclo[3.1.0]hexan-2-one

[0946] To a solution of crude ethyl3-(3-hexyl-6-methyl-2-oxo-3-azabicyclo[3.1.0]hex-6-yl)benzenecarboximidoate(Preparation 42, 700 mg, 1.86 mmol) in methanol (5 ml) was added formicacid hydrazide (123 mg, 2.05 mmol) and the mixture was heated underreflux for 90 min. After cooling to room temperature, the solvent wasremoved in vacuo and the residue was heated to 150° C. for 12 h. Themixture was cooled and purified directly by silica column chromatographyeluting with ethyl acetate:methanol (95:5) to afford the title compound(400 mg, 64%) as a colourless gum.

[0947] NMR (CDCl₃) δ: 0.83-0.94 (m, 3H), 1.22-1.38 (m, 9H),1.44-1.58 (m,2H), 2.17 (t, 1H), 2.41 (m, 1H), 3.10-3.38 (m, 3H), 3.68 (dd, 1H),7.36-7.43 (m, 2H), 7.92-7.99 (m, 2H), 8.20 (s, 1H)

[0948] Preparation 44

3-Hexyl-6-[3-(1H-imidazol-2-yl)phenyl]-6-methyl-3-azabicyclo[3.1.0]hexan-2-one

[0949] To a solution of ethyl3-(3-hexyl-6-methyl-2-oxo-3-azabicyclo[3.1.0]hex-6-yl)benzenecarboximidoatehydrochloride (Preparation 42, 528 mg, 1.45 mmol) in methanol (6 ml) atroom temperature was added aminoacetaldehyde dimethylacetal (0.16 g,1.52 mmol). The mixture was heated under reflux for 90 min, cooled toroom temperature and the solvent was removed in vacuo. The crude residuewas dissolved in 6N hydrochloric acid (8 ml) and the mixture was heatedto 80° C. for 30 min and then left at room temperature for 2 h. Themixture was diluted with water (5 ml), the pH was adjusted to 9 using 5Nsodium hydroxide solution and the aqueous solution was extracted withethyl acetate (3×20 ml). The combined extracts were dried (MgSO₄),filtered and concentrated in vacuo. The crude residue was purified bysilica column chromatography eluting with ethyl acetate:methanol:ammoniasolution (0.880) (90:10:1) to afford the title compound (190 mg, 39%) asa colourless oil.

[0950] NMR (CDCl₃) δ: 0.82-0.91 (m, 3H), 1.18 (s, 3H), 1.24-1.38 (m,6H), 1.44-1.58 (m, 2H), 2.0 (m, 1H), 2.18 (m, 1H), 3.08-3.38 (m, 3H),3.62 (dd, 1H), 7.12-7.35 (m, 4H), 7.58 (s, 1H), 7.82 (d, 1H).

[0951] Preparation 45

N-[3-(3-Hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]acetamide

[0952] To a solution of3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation12, 1.30 g, 4.8 mmol) and triethylamine (3.34 ml, 24.0 mmol) indichloromethane (30 ml) at room temperature was slowly added acetylchloride (0.48 ml, 6.72 mmol). The mixture was stirred at roomtemperature ovenight and then saturated ammonium chloride solution (50ml) was added. The two layers were separated and the aqueous layer wasextracted with dichloromethane (3×20 ml). The combined extracts weredried (MgSO₄), filtered and concentrated in vacuo. The crude residue waspurified by silica column chromatography eluting with ethylacetate:methanol:ammonia solution (0.880) (90:10:1) to afford the titlecompound (1.5 g, 100%) as a colourless gum.

[0953] NMR (CDCl₃) δ: 0.82-0.95 (m, 3H), 1.25-1.38 (m, 6H), 1.38-1.43(m, 2H), 1.50 (s, 3H), 1.76 (m, 2H), 2.18 (s, 3H), 2.42 (m, 2H), 2.78(m, 2H), 2.98 (m, 2H), 7.00 (d, 1H), 7.10-7.30 (m, 3H), 7.38 (s, 1H).

[0954] Preparation 46

N-[5-(3-Hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)-2-nitrophenyl]-acetamide

[0955] To a solution ofN-[3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]acetamide(Preparation 45, 1.5 g, 4.78 mmol) in acetonitrile (20 ml) at 0° C. wasadded nitronium tetrafluoroborate (1.0 g, 7.53 mmol) in several portionsover 5 minutes. The mixture was stirred at 0° C. for 30 minutes and thensaturated sodium hydrogen carbonate solution (30 ml) was added. Theaqueous mixture was extracted with ethyl acetate (3×15 ml) and thecombined extracts were dried (MgSO₄), filtered and concentrated invacuo. The crude residue was purified by silica column chromatographyeluting with ethyl acetate:hexane (50:50) to afford the title compound(534 mg, 32%) as pale yellow platelets.

[0956] NMR (CDCl₃) δ: 0.82-0.92 (m, 3H), 1.25-1.45 (m, 8H), 1.58 (s,3H), 1.80 (m, 2H), 2.28 (s, 3H), 2.40 (t, 2H), 2.78 (m, 2H), 3.02 (m,2H), 7.00 (d, 1H), 8.09 (d, 1H), 8.64 (s, 1H), 10.4 (broad s, 1H)

[0957] MS (thermospray): m/z [MH⁺] 360.2; C₂₀H₂₉N₃O₃+H requires 360.2

[0958] Preparation 47

5-(3-Hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)-2-nitrophenylamine

[0959] To a solution of potassium hydroxide (100 mg, 1.79 mmol) inmethanol (5.0 ml) and water 2.0 ml) was addedN-[5-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)-2-nitrophenyl]acetamide(Preparation 46, 534 mg, 1.49 mmol) in methanol (5 ml). The mixture washeated under reflux for 30 minutes and then was allowed to cool. Thesolvent was removed in vacuo, water (5 ml) was added and the aqueoussolution was extracted with ethyl acetate (3×5 ml). The combinedextracts were dried (MgSO₄), filtered and concentrated in vacuo toafford the title compound (360 mg, 76%) as a crude oil which was usedwithout further purification.

[0960] NMR (CDCl₃) δ: 0.82-0.95 (m, 3H), 1.25-1.45 (m, 8H), 1.56 (s,3H), 1.79 (m, 2H), 2.42 (t, 2H), 2.80 (m, 2H), 3.00 (m, 2H), 6.00 (broads, 2H), 6.53 (d, 1H), 6.63 (s, 1H), 7.99 (d, 1H)

[0961] Preparation 48

2-Amino-4-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl) Phenylamine

[0962] To a solution of5-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)-2-nitrophenylamine(Preparation 47, 360 mg, 1.14 mmol) in ethanol (15 ml) was added 10%palladium on carbon (50 mg). The mixture was placed under an atmosphereof hydrogen (50 psi, 345 kPa) and heated at 50° C. for 16 hours. Themixture was then cooled and filtered through Celite™, washing withethanol. The filtrate was concentrated in vacuo to give the crude titlecompound (328 mg, 100%) as a yellow oil which was used without furtherpurification.

[0963] NMR (CDCl₃) δ: 0.82-0.92 (m, 3H), 1.25-1.38 (m, 6H), 1.42-1.60(m, 5H), 1.80 (m, 2H), 2.45-2.60 (m, 2H), 2.80-3.10 (m, 4H), 3.35 (broads, 4H), 6.57-6.62 (m, 3H)

[0964] MS (thermospray): m/z [MH⁺] 288.4; C₁₈H₂₉N₃+H requires 288.2

[0965] Preparation 49

[0966] To sulfuric acid oleum (6 ml) in nitromethane (15 ml) was addeddropwise over 30 min isopropyl isocyanate at 0° C. The reaction mixturewas heated under reflux for 30 min and then cooled to room temperature,the solid was collected by suction filtration and washed with diethylether. The solid was dissolved in toluene (6 ml) and phosphoruspentachloride (7.58 g, 36.4 mmol) was added. The reaction mixture washeated under reflux for 2.5 h and the solvent was removed in vacuo. Thecrude product was distilled to give the title compound as an oil(b.p.80° C. at 0.5 mmHg).

[0967] NMR (CDCl₃): 1.35 (d, 6H), 3.9 (m, 1H), 5.4 (br, 1H).

[0968] Preparation 50

[0969] Ethyl3-(chloromethyl)-2-methyl-2-(3-nitrophenyl)cyclopropanecarboxylate(Preparation 5, 1 g, 3.36 mmol) in allylamine (1.15 g, 20.1 mmol) washeated in a sealed tube at 150° C. for 16 h. After cooling the reactionmixture was concentrated in vacuo. The residue was dissolved indichloromethane and washed with saturated aqueous sodium hydrogencarbonate solution. The organic extracts were dried (Na₂SO₄) andconcentrated in vacuo to give the crude product as a yellow oil (0.92 g,100%).

[0970] NMR (CDCl₃, selected data for the free base): 1.4 (s, 3H), 2.1(m, 1H), 2.4 (m, 1H), 3.35 (m, 1H), 3.7 (m, 1H), 3.8-4.0 (m, 2H),5.2-5.3 (m, 2H), 5.75 (m, 1H), 7.5 (t, 1H), 7.65 (d, 1H), 8.05 (d, 1H),8.15 (s, 1H).

[0971] MS (ES): M/Z (MH⁺) 273.0; C₁₅H₁₆N₂O₃+H requires 273.1.

[0972] Preparation 51

[0973] To a solution of3-allyl-6-methyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexan-2-one(Preparation 50, 10.2 g, 37.5 mmol) in ethanol (850 ml) and water (150ml) was added iron powder (18.9 g, 337.5 mmol) and calcium chloride (2.1g, 18.7 mmol). The reaction mixture was refluxed for 5 h, and thenfiltered to remove the iron powder. The reaction mixture wasconcentrated in vacuo and the residue was dissolved indichloromethane:methanol (85: 15), filtered and then concentrated invacuo, dissolved in tetrahydrofuran, filtered and then concentrated invacuo to give the title compound as a pale yellow foam (9 g, 99%).

[0974] NMR (CDCl₃, selected data for the free base): 1.2 (s, 3H), 2.05(m, 1H), 2.2 (m, 1H), 3.2 (m, 1H), 3.6 (m, 1H), 3.7-3.8 (m, 2H), 5.1-5.2(m, 2H), 5.7 (m, 1H), 6.5 (d, 1H), 6.6-6.7 (m, 2H), 7.0 (t, 1H).

[0975] Preparation 52

[0976] To dry tetrahydrofuran (300 ml) under nitrogen was added dropwiselithium aluminium hydride (1M in tetrahydrofuran, 75 ml, 75 mmol). Tothis solution,3-allyl-6-(3-aminophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one(Preparation 51, 9.0 g, 37.1 mmol) dissolved in tetrahydrofuran (200ml), was added dropwise at 0° C. The reaction mixture was stirred for 1h and then heated to 50° C. for 3 h. The reaction mixture was quenchedwith water (150 ml) and solid sodium hydrogen carbonate was added. Theslurry was extracted with ethyl acetate and then dichloromethane. Theorganic extracts were combined and dried (Na₂SO₄) and then concentratedin vacuo to give the title compound as a thick yellow oil (8.5 g, 100%).

[0977] NMR (CDCl₃ selected data for the free base): 1.5 (s, 3H), 1.8 (m,2H), 2.85 (m, 2H), 2.95 (m, 2H), 3.2 (m, 2H), 5.0-5.3 (m, 2H), 5.9 (m,1H), 6.5 (d, 1H), 6.6 (s, 1H), 6.65 (d, 1H), 7.1 (t, 1H).

[0978] Preparation 53

[0979] A stirred mixture ofN-[3-(3-allyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Example 56, 1.90 g, 6.19 mmol), tetrakis(triphenylphosphine)palladium(0) (71.8 mg, 62.1 μmol) and N,N-dimethylbarbituric acid (2.91 g, 18.6mmol) in dichloromethane (15 ml) was degassed and then heated to 35° C.under nitrogen for 3 h. The solution was rapidly stirred with aqueoushydrochloric acid solution (2M, 40 ml) and the aqueous portion wasseparated, this process was repeated. The combined aqueous layers werewashed with dichloromethane (7×50 ml), and then concentrated in vacuo togive the hydrochloride salt of the title compound as an off white solid(1.40 g, 74%).

[0980] NMR (d₆-DMSO, selected data for the hydrochloride salt): 1.25 (s,3H), 2.15 (m, 2H), 2.95 (s, 3H), 3.2 (m, 2H), 3.6 (m, 2H), 6.95-7.05 (m,2H), 7.1 (s, 1H), 7.2 (t, 1H), 9.6 (br, 1H).

[0981] MS (ES): M/Z (MH⁺) 267.1; C₁₃H₁₈N₂O₂S+H requires 267.1.

[0982] Preparation 54

[0983] Maleic anhydride (39.4 g, 0.40 mol) was partly dissolved intoluene (1 l) to form a milky suspension. N-hexylamine (53 ml, 0.40 mol)was diluted with toluene (500 ml) and added dropwise over a period of1.5 h. After 2 h, the reaction mixture was filtered and the titlecompound was obtained as a white solid (76.4 g, 96%) after drying for 16h in a vacuum oven at 40° C.

[0984] NMR (CDCl₃, selected data for the free base) 0.8 (m, 3H), 1.2-1.4(m, 6H), 1.6 (m, 2H), 3.3 (m, 2H) 6.25 (d, 1H), 6.45 (d, 1H), 7.8 (br,1H).

[0985] Preparation 55

[0986] Concentrated nitric acid (20 ml) was added cautiously withcooling to concentrated sulphuric acid (50 ml) maintaining a temperatureof −5° C. Another solution of 2-methyl-1-phenyl-1-propanone (29.6 g, 0.2mol) in concentrated sulphuric acid (70 ml) was made up with shaking,keeping the temperature at −5° C. The former nitric acid/sulphuric acidsolution was added portionwise over 30 min to the latter solution ofketone in sulphuric acid keeping the temperature at −10° C.+/−5° C.during the addition and for a subsequent 30 min. The reaction mixturewas poured onto crushed ice (1 l) and then extracted with diethyl ether(3×100 ml). The organic extracts were washed with water (300 ml) andthen brine (300 ml), dried (Na₂SO₄) and then concentrated in vacuo. Thecrude product was obtained as an orange oil (40 g) which was purified bychromatography on silica gel (450 g) eluting with hexane:diethyl ether(9:1) to give the title compound as a pale yellow solid (16.3 g, 42%),m.p.33-35° C.

[0987] NMR (CDCl₃, selected data for the free base): 1.25 (d, 6H), 3.6(m, 1H), 7.65 (t, 1H), 8.25 (d, 1H), 8.4 (d, 1H), 8.9 (s, 1H).

[0988] Preparation 56

[0989] 4-(Hexylamino)-4-oxo-2-butenoic acid (Preparation 54, 75.8 g,0.38 mol) was partially dissolved in acetic anhydride (1.5 l) and sodiumacetate (125.6 g, 0.19 mol) was added in one portion. The reactionmixture was gradually heated to 110° C. for 4 h. Acetic anhydride wasremoved in vacuo and the title compound was obtained by vacuumdistillation of the crude residue to give a colourless oil (49.8 g, 72%)which partially crystallised upon standing.

[0990] NMR (CDCl₃, selected data for the free base): 0.85 (m, 3H),1.2-1.4 (m, 6H), 1.6 (m, 2H), 3.5 (m, 2H), 6.7 (s, 2H).

[0991] Preparation 57

[0992] To a partially dissolved solution of2-methyl-1-(3-nitrophenyl)-1-propanone (Preparation 55, 1.0 g, 5.2 mmol)in industrial methylated spirits (6 ml) was added dropwise hydrazinehydrate monohydrate (0.5 ml, 10.4 mmol). The reaction mixture wasrefluxed for 16 h, before cooling to room temperature and pouring intoice and water (50:50, 15 ml) giving a very fine white precipitate in ayellow solution. The mixture was extracted with diethyl ether (2×50 ml),the combined organic extracts were washed with brine and dried (MgSO₄),before concentrating to give an amber oil. The crude product waspurified by chromatography on silica gel eluting withdichloromethane:ethyl acetate (19:1) to give the title compound as amixture of cis and trans hydazones (0.54 g, 50%).

[0993] NMR (CDCl₃, selected data for the free base, 2:1 mixture ofisomers): 1.1 (d, 4H), 1.25 (d, 2H), 2.75 (m, 0.6), 3.2 (m, 0.4), 4.95(br, 1.2), 5.6 (br, 0.8), 7.45-8.3 (m, 4H).

[0994] MS (ES): M/Z (MH⁺) 208.2; C₁₀H₁₃N₃O₂+H requires 208.1.

[0995] Preparation 58

[0996] 2-Methyl-1-(3-nitrophenyl)-1-propanone hydrazone (Preparation 57,0.52 g, 2.5 mmol) was dissolved in dioxan (10 ml) and manganese dioxide(grade CMD-1 from Sumitomo, 5.2 g, 60.0 mmol) was added portionwise andthe reaction mixture was stirred at room temperature for 20 minutes.This solution was filtered over a pad of Celite® dropwise, directly intoa solution of 1-hexyl-1H-pyrrole-2,5-dione (Preparation 56, 0.54 g, 3.0mmol) in dioxan (10 ml). The Celite® pad was washed with dioxan (40 ml)to ensure complete addition of the reactants and then the reactionmixture was stoppered and stirred for 72 h. The reaction mixture waspurified by chromatography using a Biotage Flash 40S™ cartridge packedwith silica gel (40 g), eluting with petroleum ether:ethyl acetate(4:1). The title compound was obtained as a yellow solid (0.65 g, 67%).

[0997] NMR (CDCl₃, selected data for the free base): 0.8-1.4 (m, 15H),1.8 (m, 2H), 2.7 (m, 1H), 3.1-3.25 (m, 3H), 5.85 (d, 1H), 7.6 (m, 2H),8.2 (m, 2H).

[0998] Preparation 59

[0999]5-Hexyl-3-isopropyl-3(3-nitrophenyl)-3a,6a-dihydropyrrolo(3,4-c)pyrazole-4,6(3H,5H)-dione(Preparation 58, 0.65 g, 1.6 mmol) was dissolved in dioxan (25 ml) andheated under reflux for 3 h. The solvent was removed in vacuo and theoily residue dried in vacuum for 16 h at room temperature to give thecrude product as a yellow solid. The crude product was purified bychromatography on a Biotage Flash 12M™ cartridge packed with silica gel(8 g), eluting with hexane:ethyl acetate (9:1) to give the titlecompound (0.60 g, 100%).

[1000] NMR (CDCl₃, selected data for the free base): 0.85 (m, 3H), 0.95(d, 6H), 1.2-1.4 (m, 6H), 1.55 (m, 2H), 1.7 (m, 1H), 2.8 (s, 2H), 3.45(m, 2H), 7.5 (t, 1H), 7.65 (d, 1H), 8.2 (m, 2H).

[1001] MS (TSP): M/Z (MNH₄ ⁺) 376.4; C₂₀H₂₆N₂O₄+NH₄ ⁺ requires 376.2.

[1002] Preparation 60

[1003] To a stirred solution of3-hexyl-6-isopropyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione(Preparation 59, 0.57 g, 1.6 mmol) in tetrahydrofuran (6 ml), undernitrogen, was added borane tetrahydrofuran complex (1M intetrahydrofuran, 3.0 ml, 3.0 mmol) and the reaction mixture was heatedunder reflux for 2 h. The reaction mixture was cooled to roomtemperature before the addition of further borane tetrahydrofurancomplex (1M in tetrahydrofuran, 3.0 ml, 3.0 mmol). After 20 min, thereaction mixture was cooled to room temperature and methanol (8 ml) wasadded and then the reaction mixture was once more heated under refluxfor 6 h. The reaction mixture was concentrated. in vacuo and the residuewas dried under vacuum at room temperature. The residue was treated withdichloromethane (4 ml), filtered and purified by chromatography on aBiotage Flash40S™ cartridge packed with silica gel (40 g) eluting withhexane:ethyl acetate (6:1). The title compound was obtained initially asa yellow oil which crystallised upon standing (0.2 g, 40%).

[1004] NMR (CDCl₃, selected data for the free base): 0.8-1.0 (m, 9H),1.25-1.4 (m, 6H), 1.4 (m, 2H), 1.8 (m, 2H), 2.45 (m, 2H), 2.6 (m, 1H),2.85 (m, 2H), 3.05 (m, 2H), 7.4 (t, 1H), 7.6 (d, 1H), 8.0-8.15 (m, 2H).

[1005] Preparation 61

[1006] To a stirred suspension of3-hexyl-6-isopropyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane(Preparation 60, 0.18 g, 0.54 mmol), ethanol (15 ml) and iron powder(0.27 g, 4.88 mmol) was added calcium chloride (0.06 gm 0.54 mmol) inwater (3 ml). The reaction mixture was heated under reflux for 3 h andthen filtered through a pad of Celite®, the mother liquors wereconcentrated in vacuo. The residue was dissolved in dichloromethane andfiltered again through a Sep-Pak® Plus cartridge containing silica (1.5g), (Water Division Millipore), to remove any residual iron salts andthen concentrated to give the crude title compound as a yellow solid(0.17 g, 100%).

[1007] NMR (CDCl₃, selected data for the free base): 0.75-0.85 (m, 9H),1.2-1.4 (m, 6H), 6.4-6.6 (m, 3H), 7.0 (t, 1H).

[1008] MS (APCI): M/Z (MH⁺) 301.1; C₂₀H₃₂N₂+H⁺ requires 301.3.

[1009] Preparation 62

[1010] Concentrated nitric acid (40 ml) was added cautiously withcooling to concentrated sulphuric acid (100 ml) maintaining atemperature of −5° C. Another solution of butyrophenone (59.2 g, 0.47mol) in concentrated sulphuric acid (140 ml) was made up with shaking,keeping the temperature at −5° C. (+/−5° C.). The former nitricacid/sulphuric acid solution was added portionwise over 45 min to thelatter solution of ketone in sulphuric acid keeping the temperature at−10° C.+/−5° C. during the addition and for a subsequent 30 min. Thereaction mixture was poured onto crushed ice (1.5 l) and then extractedwith diethyl ether (200 ml and then 3×100 ml). The combined organicextracts were washed with water and then aqueous saturated sodiumhydrogen carbonate solution and dried (MgSO₄) before concentrating invacuo. The crude yellow oil crystallised after 16 h and was thenpurified by chromatography on silica gel (1 kg) eluting withhexane:diethyl ether (9:1) to give the title compound as a white solid(9.1 g, 10%).

[1011] NMR (CDCl₃, selected data for the free base): 1.05 (t, 3H), 1.8(m, 2H), 3.0 (t, 2H), 7.65 (t, 1H), 8.25 (d, 1H), 8.4 (d, 1H), 8.9 (s,1H).

[1012] Preparation 63

[1013] To a partially dissolved solution of 1-(3-nitrophenyl)-1-butanone(Preparation 62, 9.0 g, 46.6 mmol) in industrial methylated spirits (60ml) was added dropwise hydrazine hydrate monohydrate (4.5 ml, 93.2mmol). The reaction mixture was refluxed for 6 h, before cooling to 0°C. and adding water (60 ml) dropwise with stirring. The mixture wascooled in a refrigerator for 16 h and the orange crystals (7.5 g) soformed were removed by filtration. The filtrate was diluted with water(350 ml) and extracted with dichloromethane (3×150 ml), the combinedorganic extracts were dried (Na₂SO₄), and concentrated to give an orangeoil (1.8 g). Both the crystals and oil were combined to give the desiredtitle compound (9.3 g, 96%).

[1014] NMR (CDCl₃, selected data for the free base): 1.1 (m, 3H), 1.6(m, 2H), 2.6 (m, 2H), 7.5 (t, 1H), 8.0 (d, 1H), 8.1 (d, 1H), 8.5 (s,1H).

[1015] MS (TSP): M/Z (MH⁺) 207.9; C₁₀H₁₃N₃O₂+H requires 208.1.

[1016] Preparation 64

[1017] 1-(3-Nitrophenyl)-1-butanone hydrazone (Preparation 63, 1.0 g,4.8 mmol) was dissolved in dioxan (20 ml) and cooled to 10° C.,manganese dioxide (grade CMD-1 from Sumitomo, 10 g, 117 mmol) was addedportionwise. After the addition was complete, te reaction mixture wasstirred at room temperature for 30 minutes. This suspension was filteredover a pad of Celite® directly into a solution of1-hexyl-1H-pyrrole-2,5-dione (Preparation 56, 0.88 g, 4.5 mmol) indioxan (20 ml). The Celite® pad was washed with dioxan (125 ml) and thenstirred at room temperature for 20 h. The reaction mixture wasconcentrated in vacuo to give a crude orange oil. Methanol (8 ml) wasadded and the mixture was cooled to 0° C. and upon scratching a whitesolid precipitated. The solid was filtered off and washed with coldmethanol to give the pure product, the mother liquors were concentratedin vacuo and treated again with methanol under the procedure describedabove to give further product. The title compound was obtained as awhite solid (0.28 g, 16%).

[1018] NMR (CDCl₃, selected data for the free base): 0.8 (m, 3H), 0.9(m, 3H), 1.2-1.4 (m, 8H), 1.6 (m, 2H), 1.7 (m, 2H), 2.8 (m, 2H), 3.5 (m,2H), 7.5 (t, 1H), 7.65 (d, 1H), 8.1 (d, 1H), 8.2 (s, 1H).

[1019] Preparation 65

[1020] To a stirred solution of3-hexyl-6-(3-nitrophenyl)-6-propyl-3-azabicyclo[3.1.0]hexane-2,4-dione(Preparation 64, 0.28 g, 0.78 mmol) in tetrahydrofuran (3 ml), undernitrogen, was added borane tetrahydrofuran complex (1M intetrahydrofuran, 1.7 ml, 1.7 mmol) and the reaction mixture was heatedunder reflux for 2 h. The reaction mixture was cooled to roomtemperature, methanol (1.5 ml) was added and then the reaction mixturewas heated under reflux for 16 h. The reaction mixture was concentratedin vacuo and the residue was dissolved in methanol (14 ml) and refluxedfor 5 h. The reaction mixture was concentrated in vacuo, methanol (14ml) was added and the reaction mixture was refluxed for a further 3 hbefore concentrating in vacuo. The crude residue was purified bychromatography on a Biotage Flash12M™ cartridge packed with silica gel(8 g), eluting with hexane:ethyl acetate (4:1) to give the titlecompound as a yellow oil (0.2 g, 79%).

[1021] NMR (CDCl₃, selected data for the free base): 0.8-1.0 (m, 6H),1.15-1.5 (m, 10H), 1.8 (m, 2H), 2,0 (m, 2H), 2.4 (m, 2H), 2.8 (m, 2H),3.0 (m, 2H), 7.4 (t, 1H), 7.6 (d, 1H), 8.0 (d, 1H), 8.1 (s, 1H).

[1022] MS (ES): M/Z (MH⁺) 331.1; C₂₀H₃₀N₂O₂+H requires 331.2.

[1023] Preparation 66

[1024] To a stirred suspension of3-hexyl-6-(3-nitrophenyl)-6-propyl-3-azabicyclo[3.1.0]hexane(Preparation 65, 2.60 g, 7.2 mmol), ethanol (150 ml) and iron powder(0.41 g, 73.2 mmol) was added calcium chloride (1.5 g 13.0 mmol) inwater (50 ml). The reaction mixture was heated under reflux for 16 h.The reaction mixture was cooled to room temperature, filtered through apad of Celite®, and the mother liquors were concentrated in vacuo. Theresidue was dissolved in dichloromethane and filtered through a pad ofsodium sulphate to give upon concentration the title compound as ayellow oil (2.17 g, 100%).

[1025] NMR (CDCl₃, selected data for the free base): 0.8-1.0 (m, 6H),1.2-1.4 (m, 10H), 1.6-1.8 (m, 4H), 2.0 (m, 2H), 2.8 (m, 2H), 3.6 (m,2H), 6.45-6.55 (m, 2H), 6.6 (d, 1H), 7.0 (m, 1H).

[1026] MS (ES): M/Z (MH⁺) 301.2; C₂₀H₃₂N₂+H⁺ requires 301.3.

[1027] Preparation 67

[1028] A solution of sodium nitrite (0.25 g, 3.6 mmol) dissolved inwater (4 ml) was added to3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation12, 0.43 g, 1.6 mmol) dissolved in aqueous hydrochloric acid (2.0 M, 4ml) at 0° C. After 15 min at 0° C., the reaction mixture was added topotassium iodide (0.61 g, 3.69 mmol) in water (4 ml) at 0° C. with rapidstirring. The reaction mixture was stirred for 30 min at roomtemperature and was then heated to 90° C. for 5 min. The reactionmixture was cooled to room temperature and then poured cautiously ontosolid sodium hydrogen carbonate with cooling. After 12 h, the reactionmixture was extracted with diethyl ether and then ethyl acetate and thecombined organic extracts were washed with aqueous sodium thiosulphatesolution, dried (MgSO₄) and then concentrated in vacuo. The cruderesidue was purified by chromatography on silica gel eluting withhexane:ethyl acetate (10:1 and then 3:1) to give the title compound(0.18 g, 24%).

[1029] NMR (CDCl₃, selected data for the free base): 0.85 (m, 3H),1.2-1.4 (m, 9H), 1.5 (m, 2H), 2.05 (m, 1H), 2.25 (m, 1H), 3.05-3.3 (m,3H), 3.65 (m, 1H), 7.0 (t, 1H), 7,2 (d, 1H), 7.5 (d, 1H), 7.65 (s, 1H).

[1030] MS (TSP): M/Z (MH⁺) 398.1; C₁₈H₂₄ ¹²⁹INO+H⁺ requires 398.1.

[1031] Preparation 68

[1032] To tris(dibenzylideneacetone)dipalladium (0) (4.4 mg, 4.80 μmol)in tetrahydrofuran (1 ml) at room temperature was added triphenylarsine(5.9 mg, 19.2 μmol). After 5 min, 2-(tributylstannyl)pyridine (0.10 g,0.29 mmol) in tetrahydrofuran (1 ml) was added followed by3-hexyl-6-(3-iodophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one(Preparation 67, 77 mg, 0.19 mmol) in tetrahydrofuran (1 ml). Thereaction mixture was stirred at room temperature for 16 h and thenrefluxed for 2 h. The cooled reaction mixture was concentrated in vacuoand chromatographed on silica gel eluting with hexane:ethyl acetate (1:1then 0:1) to give the title compound as a colourless oil (67 mg, 100%).

[1033] NMR (CDCl₃, selected data for the free base): 0.9 (m, 3H),1.2-1.4 (m, 6H), 1.5-1.7 (m, 5H), 2.1 (m, 1H), 2.4 (m, 1H), 3.1-3.4 (m,3H), 3.7 (m, 1H), 7.2-7.3 (m, 2H), 7.35-7.45 (m, 2H), 7.65-7.85 (m, 2H),8.0 (m, 1H), 8.7 (m, 1H).

[1034] MS (TSP): M/Z (MH⁺) 348.9; C₂₃H₂₈N₂O+H requires 349.2.

[1035] Preparation 69

[1036] To tris(dibenzylideneacetone)dipalladium (0) (4.5 mg, 4.91 μmol)in tetrahydrofuran (1 ml) at room temperature was added triphenylarsine(5.9 mg, 19.2 μmol). After 5 min, 2-(tributylstannyl)thiophene (0.10 g,0.27 mmol) in tetrahydrofuran (1 ml) was added followed by3-hexyl-6-(3-iodophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one(Preparation 67, 78 mg, 0.19 mmol) in tetrahydrofuran (1 ml). Thereaction mixture was stirred at room temperature for 16 h and thenrefluxed for 2 h. The cooled reaction mixture was concentrated in vacuoand chromatographed on silica gel eluting with hexane:ethyl acetate(2:1) to give the title compound as a colourless oil (68 mg, 98%).

[1037] NMR (CDCl₃, selected data for the free base): 0.9 (m, 3H),1.2-1.4 (m, 9H), 1.5 (m, 2H), 2.15 (m, 1H), 2.4 (m, 1H), 3.1-3.4 (m,3H), 3.7 (m, 1H), 7.05 (m, 1H), 7.2-7.35 (m, 4H), 7.45 (d, 1H), 7.55 (s,1H).

[1038] MS (TSP): M/Z (MH⁺) 354.2; C₂₂H₂₇NOS+H requires 354.2.

[1039] Preparation 70

[1040] A solution of iodine (22.5 g, 88 mmol) in 20% aqueous potassiumiodide (150 ml) was added dropwise to a stirred solution of imidazole(3.4 g, 49 mmol) in aqueous sodium hydroxide solution (1M, 300 ml) atroom temperature. After stirring for 16 h, acetic acid was added toneutralise the reaction mixture. The white precipitate formed wasfiltered off and washed with water before dissolving in ethanol andconcentrating in vacuo to give the title compound (7.7 g, 54%).

[1041] NMR (d₆-DMSO, selected data for the free base: 7.8 (br, 1H),12.75 (br, 1H).

[1042] MS (TSP): M/Z (MH⁺) 320.8; C₃H₂ ¹²⁹I₂N₂+H requires 320.8.

[1043] Preparation 71

[1044] To a solution of 4,5-diiodo-1H-imidazole (Preparation 70, 7.7 g,24 mmol) in ethanol (80 ml) and water (20 ml) was added solid sodiumsulfite heptahydrate (20 g, 79 mmol). The reaction mixture was heated atreflux for 16 h, cooled, and the solid by-products were removed byfiltration. The filtrate was then concentrated in vacuo and theresultant solid was dried by suction. The crude residue wasrecrystallised from dichloromethane to give the title compound as awhite solid (4.6 g, 64%).

[1045] NMR (CDCl₃, selected data for the free base: 7.0 (s, 1H), 7.5 (s,1H).

[1046] MS (TSP): M/Z (MH⁺): 195.2; C₃H₃ ¹²⁹IN₂+H requires 194.9.

[1047] Preparation 72

[1048] To 4-iodo-1H-imidazole (Preparation 71, 3.0 g, 15.3 mmol) inN,N-dimethylformamide (25 ml) was added triphenylmethyl chloride (4.72g, 16.9 mmol) and then triethylamine (2.5 ml, 18.4 mmol). After stirringat room temperature for 2.5 h, water (200 ml) was added and the reactionmixture was filtered and washed with water. The crude solid waschromatographed on silica gel eluting with hexane:ethyl acetate (5:1 andthen 2:1). The material was then recrystallised from hexane anddichloromethane to give the title compound as a white solid (4.0 g,59%).

[1049] NMR (CDCl₃, selected data for the free base: 6.9 (m, 1H), 7.0-7.2(m, 6H), 7.25-7.4 (m, 10H).

[1050] MS (TSP): M/Z (MH⁺): 436.3; C₂₂H₁₇ ¹²⁹IN₂+H requires 437.1.

[1051] Preparation 73

[1052] To 4-iodo-1-triphenylmethyl-1H-imidazole (Preparation 72, 0.44 g,0.10 mmol) in dichloromethane (8.0 ml) at room temperature was addedslowly ethyl magnesium bromide (3.0 M in diethyl ether, 0.35 ml, 1.0mmol). After 30 min, tributyltin chloride (0.3 ml, 1.1 mmol) was addedand the reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was quenched with saturated aqueous ammonium chloridesolution (10 ml) and the product was extracted with dichloromethane(3×10 ml). The combined organic layers were dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with hexane:ethyl acetate (10:1 and then 5:1) togive the title compound (59 mg, 98%).

[1053] NMR (CDCl₃, selected data for the free base: 0.8-1.0 (m, 9H),1.2-1.7 (m, 18H), 6.75 (m, 1H), 7.1-7.2 (m, 6H), 7.25-7.4 (m, 9H), 7.6(s, 1H).

[1054] Preparation 74

[1055] To tris(dibenzylideneacetone)dipalladium (0) (8.7 mg, 9.5 μmol)in tetrahydrofuran (2.5 ml) at room temperature was addedtriphenylarsine (12 mg, 39.2 μmol). After 10 min, a solution of3-hexyl-6-(3-iodophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one(Preparation 67, 0.15 g, 3.8 mmol) in tetrahydrofuran (2.5 ml) wasadded. A minute later,4-(tributylstannyl)-1-triphenylmethyl-1H-imidazole (Preparation 73,0.332 g, 0.55 mmol) in tetrahydrofuran (3 ml) was added. The reactionmixture was stirred at room temperature for 30 min and then refluxed for3.5 h. The cooled reaction mixture was concentrated in vacuo andchromatographed on silica gel eluting with hexane:ethyl acetate (1:1then 0:1) to give the title compound (55 mg, 25%).

[1056] NMR (CDCl₃, selected data for the free base: 0.9 (m, 3H), 1.2-1.4(m, 9H), 1.5 (m, 2H), 2.15 (m, 1H), 0.35 (m, 1H), 3.05-3.4 (m, 3H), 3.65(m, 1H), 7.1-7.4 (m, 18H), 7.5-7.6 (m, 2H), 7.75 (m, 1H).

[1057] MS (ES): M/Z (MH⁺) 580.4; C₄₀H₄₁N₃O+H requires 580.3.

[1058] Preparation 75

[1059] To a solution of3-hexyl-6-methyl-6-[3-(1-triphenylmethyl-1H-imidazol-5-yl)phenyl]-3-azabicyclo[3.1.0]hexan-2-one(Preparation 74, 55 mg, 0.95 mmol) in methanol (1.5 ml) was addedaqueous hydrochloric acid (2M, 0.5 ml) and the mixture was heated underreflux for 16 h. The reaction mixture was then cooled to roomtemperature and poured onto solid sodium hydrogen carbonate.Dichloromethane was added, the layers were separated and the organicextracts were dried (MgSO₄) and concentrated in vacuo. The crude residuewas chromatographed on silica gel eluting with ethyl acetate to give thetitle compound as a clear oil (21 mg, 66%).

[1060] NMR (CDCl₃, selected data for the free base: 0.9 (m, 3H), 1.2-1.4(m, 9H), 1.5 (m, 2H), 2.15 (m, 1H), 2.35 (m, 1H), 3.1-3.4 (m, 3H), 3.7(m, 1H), 7.2 (d, 1H), 7.3 (t, 1H), 7.35 (s, 1H), 7.55 (d, 1H), 7.65 (s,1H), 7.75 (s, 1H).

[1061] MS (ES): M/Z (MH⁺) 338.3; C₂₁H₂₇N₃O+H requires 338.2.

[1062] Preparation 76

[1063] To 3-acetylpyridine (6.1 g, 52 mmol) in industrial methylatedspirits (50 ml) was added dropwise hydrazine hydrate monohydrate (3.11ml, 0.1 mol). The reaction mixture was refluxed for 4 h, before coolingto room temperature and stirring for 16 h. Water (25 ml) was added andthe volatile organics were removed in vacuo. The predominantly aqueousresidual liquor was extracted with ethyl acetate, and the combinedorganic extracts were dried (Na₂SO₄) and concentrated to give a yellowoil (5.4 g, 80%) which was taken forward without further purification.

[1064] NMR (CDCl₃, selected data for the free base): 2.1 (s, 3H), 5.5(br, 2H), 7.2 (m, 1H), 7.9 (m, 1H), 8.45 (m, 1H), 8.8 (s, 1H).

[1065] MS (ES): M/Z (2M+H⁺) 270.7; C₁₄H₁₉N₆+H requires 271.2.

[1066] Preparation 77

[1067] 1-(3-Pyridinyl)-1-ethanone hydrazone (Preparation 76, 5.0 g, 40.0mmol) was dissolved in dioxan (250 ml) and manganese dioxide (6.4 g,40.0 mmol) was added portionwise followed by a saturated solution ofpotassium hydroxide in ethanol (2 ml). The reaction mixture was stirredat room temperature for 4 h and then filtered through a pad of Celite®.The filtrate was added to 1-benzyl-1H-pyrrole-2,5-dione (7.5 g, 40.0mmol) and the reaction mixture was stirred for 16 h at room temperatureand was then refluxed for 72 h. The reaction mixture was concentrated invacuo and the residue was suspended in methanol and filtered to give thetitle compound as a white solid (3 g, 25%).

[1068] NMR (CDCl₃, selected data for the free base): 1.2 (s, 3H), 2.8(s, 2H), 4.6 (s, 2H), 7.1-7.6 (m, 7H), 8.4-8.6 (m, 2H).

[1069] MS (TSP): M/Z (MH⁺) 293.0; C₁₈H₁₆N₂O₂+H requires 293.1.

[1070] Preparation 78

[1071] 1-(3-Pyridinyl)-1-ethanone hydrazone (Preparation 76, 0.69 g, 5.3mmol) was dissolved in dioxan (30 ml) and manganese dioxide (0.85 g, 5.3mmol) was added portionwise followed by a saturated solution ofpotassium hydroxide in ethanol (0.5 ml). The reaction mixture wasstirred at room temperature for 1.5 h and then filtered through a pad ofCelite®. To half of the filtrate was added 1-hexyl-1H-pyrrole-2,5-dione(Preparation 56, 0.48 g, 2.6 mmol) and the reaction mixture was heatedto 90° C. for 7 h and then cooled to room temperature for 16 h. Thereaction mixture was heated under reflux for 16 h and then stirred atroom temperature for 72 h before concentrating in vacuo. The reactionmixture was purified by chromatography using silica gel (30 g) elutingwith dichloromethane 0.880 ammonia (99:1) and thendichloromethane:methanol:0.880 ammonia (97:2:1) to afford the titlecompound (0.22 g, 29%).

[1072] NMR (CDCl₃, selected data for the free base): 0.8 (m, 3H),1.2-1.4 (m, 6H), 1.5 (s, 3H), 1.6 (m, 2H), 2.8 (m, 2H), 3.45 (m, 2H),7.3 (m, 1H), 7.65 (m, 1H), 8.5 (m, 1H), 8.6 (m, 1H).

[1073] Preparation 79

[1074] 1-(3-Pyridinyl)-1-ethanone hydrazone (Preparation 76, 0.69 g, 5.3mmol) was dissolved in dioxan (30 ml) and manganese dioxide (0.85 g, 5.3mmol) was added portionwise followed by a saturated solution ofpotassium hydroxide in ethanol (0.5 ml). The reaction mixture wasstirred at room temperature for 1.5 h and then filtered through a pad ofCelite®. To half of the filtrate was added1-(3-phenylpropyl)-1H-pyrrole-2,5-dione (Preparation 80, 0.57 g, 2.6mmol) and the reaction mixture was heated to 90° C. for 7 h and thencooled to room temperature for 16 h. The reaction mixture was heatedunder reflux for 16 h and then cooled to room temperature for 72 hbefore concentrating in vacuo. The reaction mixture was purified bychromatography using silica gel (30 g) eluting withdichloromethane:0.880 ammonia (99:1) and thendichloromethane:methanol:0.880 ammonia (97:2:1) to afford the titlecompound as an oil (230 mg, 28%).

[1075] NMR (CDCl₃, selected data for the free base): 1.5 (s, 3H), 1.9(m, 2H), 2.6 (m, 2H), 2.75 (s, 2H), 3.5 (m, 2H), 7.1-7.4 (m, 6H), 7.65(m, 1H), 8.5-8.65 (m, 2H).

[1076] Preparation 80

[1077] To stirred maleic anhydride (54.4 g, 0.55 mol) in toluene (1.5 l)was added dropwise, over 1 h, 3-phenylpropylamine (79.0 ml, 0.55 mol) intoluene (500 ml) to give a pale milky solution. After 2 h, the reactionmixture was filtered and the white solid obtained was dried for 16 h invacuo at 40° C. The solid was dissolved in acetic anhydride (2.0 l) withstirring and heated in a steam bath. After 10 min, sodium acetate (23 g,0.27 mol) was added. After 4 h, the acetic anhydride was removed invacuo, and the residual black solid was treated with unsaturated brine(400 ml) and extracted with ethyl acetate (3×). The combined organicphase was washed with saturated aqueous sodium hydrogen carbonatesolution, followed by brine. The organic layer was dried (Na₂SO₄),filtered and concentrated in vacuo to a dark solid. The crude residuewas dissolved in dichloromethane and passed through a large plug ofsilica gel eluting with dichloromethane to give a peach coloured solid.This solid was then recrystallised from diisopropyl ether, filtered anddried in vacuo at 40° C. to give the title compound as a beige solid(69.6 g, 59%).

[1078] NMR (CDCl₃, selected data for the free base): 1.95 (m, 2H), 2.65(t, 2H), 3.55 (m, 2H), 6.65 (s, 2H), 7.1-7.2 (m, 3H), 7.25-7.35 (m, 2H).

[1079] MS (ES): M/Z (MH⁺) 216; C₁₃H₁₃NO₂+H requires 216.

[1080] Preparation 81

[1081] To ethyl3-(3-hexyl-6-methyl-2-oxo-3-azabicyclo[3.1.0]hex-6-yl)benzenecarboximidoate(Preparation 42, 0.13 g, 0.34 mmol) in methanol (4 ml) at roomtemperature was added 1,2-diaminobenzene (37 mg, 0.34 mmol) and themixture was heated under reflux for 1 h and then cooled and concentratedin vacuo. The residue was dissolved in dichloromethane (10 ml) andwashed with 10% aqueous potassium carbonate solution (10 ml). Theaqueous layer was then reextracted with dichloromethane (2×8 ml). Thecombined organic layers were dried (MgSO₄) and then concentrated invacuo. The crude residue was purified by chromatography on silica geleluting with hexane:ethyl acetate (1:1 and then 1:2) to give the titlecompound as a white foam (61 mg, 47%).

[1082] NMR (CDCl₃, selected data for the free base): 0.85 (m, 3H), 1.0(s, 3H), 1.2-1.4 (m, 6H), 1.5 (m, 2H), 1.8 (m, 2H), 2.1 (m, 1H),3.05-3.2 (m, 2H), 3.35 (m, 1H), 3.5 (m, 1H), 7.15-7.35 (m, 4H), 7.6-7.8(m, 3H), 8.0 (d, 1H).

[1083] MS (ES): M/Z (MH⁺) 388.1 C₂₅H₂₉N₃O+H requires 388.2.

[1084] Preparation 82

[1085] A suspension of taurine (8.0 g, 63.9 mmol) and potassium acetate(6.7 g, 68.3 mmol) in acetic acid was refluxed for 15 min. Phthalicanhydride (10.1 g, 68.4 mmol) was added and the solution was refluxedfor 3 h. The reaction was cooled to room temperature and the solid wasfiltered off, washed with cold acetic acid and dried under vacuum at100° C. to give a white solid. The solid (14.3 g, 54.7 mmol) wassuspended in toluene (50 ml) and phosphorus pentachloride (8.12 g, 39.0mmol) was added under nitrogen. The reaction mixture was heated underreflux for 1 h. Further phosphorus pentachloride (8.12 g, 39.0 mmol) wasadded and the reaction mixture was refluxed for 2.5 h. The brownishsolution was decanted from the small amount of solid formed and thenconcentrated in vacuo, the residue was poured onto ice:water (50:50, 100ml) and filtered. The solid was dried for 16 h in vacuo at 45° C. togive a pale brown solid (6.4 g, 34%).

[1086] Preparation 83

[1087] To a solution of chlorosulphonyl isocyanate (2.4 g, 17.0 mmol) indry dichloromethane (10 ml) stirred under nitrogen at 0° C., was addedtert-butanol (2.2 g, 34.0 mmol). The reaction mixture was allowed towarm to room temperature and stirred for 16 h before the solvent wasremoved in vacuo to give a fluffy white solid.

[1088] Preparation 84

[1089] 3-Hexyl-6-methyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexan-2-one(Preparation 11, 6.3 g, 19.9 mmol) was dissolved in ethanol (250 ml),and iron powder (8.5 g, 0.15 mol), calcium chloride (0.95 g, 8.6 mmol)and water (50 ml) was added. The reaction mixture was refluxed for 2 h.The reaction mixture was cooled to room temperature and calcium chloride(0.95 g, 8.6 mmol) was added, the reaction mixture was refluxed for afurther 16 h. The reaction mixture was cooled and filtered and thenconcentrated in vacuo, the residue was partitioned betweendichloromethane and water and the organic layer separated, the aqueouslayer was extracted with dichloromethane (3×) and the combined extractswere dried (Na₂SO₄) and concentrated in vacuo. The title compound wasobtained as an orange solid (5.72 g, 100%).

[1090] NMR (CDCl₃, selected data for the free base): 0.85 (m, 3H),1.2-1.4 (m, 9H), 1.4-1.6 (m, 2H), 2.05 (m, 1H), 2.3 (m, 1H), 3.1-3.3 (m,3H), 3.6-3.7 (m, 2H), 6.5 (d, 1H), 6.6-6.7 (m, 2H), 7.05 (t, 1H).

[1091] MS (ES): M/Z (MH⁺) 287.1 C₁₈H₂₆N₂O+H requires 287.2

[1092] Preparation 85

[1093] 6-(3-Aminophenyl)-3-hexyl-6-methyl-3-azabicyclo[3.1.0]hexan-2-one(Preparation 84, 1.0 g, 3.5 mmol) was dissolved in aqueous hydrochloricacid (2.5 M, 3.5 ml) and cooled to 0° C. Sodium nitrite (0.25 g, 3.6mmol) dissolved in water (1 ml) was added to the reaction mixture andstirred for 30 min. The reaction mixture was neutralised with solidsodium carbonate and then diluted with water (5 ml). The reactionmixture was heated to 60° C. for 1 h during which time a dark brown oilformed on top of the aqueous layer. The product was extracted withdichloromethane (50 ml), and the organic extracts were dried (Na₂SO₄)and concentrated in vacuo to give a brown oil. The crude product waspurified by chromatography on silica gel (20 g) eluting with ethylacetate:hexane (1:1) to give the title compound (0.34 g, 34%).

[1094] NMR (CDCl₃, selected data for the free base): 0.85 (m, 3H),1.2-1.4 (m, 9H), 1.4-1.6 (m, 2H), 2.1 (m, 1H), 2.4 (m, 1H), 3.1-3.4 (m,3H), 3.65 (m, 1H), 6.7-6.8 (m, 2H), 6.9 (s, 1H), 7.15 (t, 1H).

[1095] MS (ES): M/Z (MH⁺) 288.2; C₁₈H₂₅NO₂+H requires 288.2.

[1096] Preparation 86

[1097] To a solution of 2-cyclohexyloxy-1-propanol (4.0 g, 28 mmol) intriethylamine (5.8 ml) and dichloromethane (250 ml) was added4-bromobenzenesulfonyl chloride (7.87 g, 31 mmol) at 0° C. undernitrogen, and the resulting mixture was stirred for 16 h at roomtemperature. The reaction mixture was washed with saturated aqueoussodium hydrogen carbonate solution, water and brine (100 ml each), dried(MgSO₄) and concentrated in vacuo to give the crude product. This waspurified by silica (200 g) column chromatography using a gradientelution of hexane:ethyl acetate (6:1 to 1: 1) to give the title compoundas a white crystalline solid (8.0 g, 80%).

[1098] NMR (CDCl₃): 1.1-1.8 (m, 14H), 3.2 (m, 2H), 3.65 (t, 2H), 4.15(t, 2H), 7.6-7.9 (m, 4H).

[1099] MS (thermospray): M/Z [MH⁺] 362.9; C₁₄H₁₉ ⁷⁹BrO₄S+H requires363.0.

[1100] Preparation 87

[1101] To a solution of 2-cyclohexyloxyethyl 4-bromobenzenesulfonate(Preparation 86, 120 mg, 0.3 mmol) in acetone (5 ml) was added sodiumiodide (90 mg, 0.6 mmol) and the reaction mixture was left to stir atroom temperature for 18 h. A further equivalent of sodium iodide wasadded and the reaction mixture was stirred at room temperature for afurther 18 h after which time the reaction mixture was heated to 80° C.for 5 h. The resulting precipitate was filtered and the filtrate wasdiluted with water (100 ml) and extracted with dichloromethane (100 ml).The extract was washed with brine (100 ml), dried (MgSO₄) andconcentrated in vacuo to give the title compound as a colourless oil (50mg, 60%).

[1102] NMR (CDCl₃): 1.1-1.9 (m, 1H), 3.1 (t, 2H), 3.7 (t, 2H).

[1103] Preparation 88

[1104] To a stirred solution of (E)-3-cyclohexyl-2-propen-1-ol (A. G. M.Barrett et al, Tetrahedron, 1996, 52, 15325), (1.47 g, 10.5 mmol) indiethyl ether (20 ml) and pyridine (1 ml) was added phosphorustribromide (1.40 ml, 15 mmol) dropwise at room temperature under anatmosphere of nitrogen. After 16 h, the reaction mixture was carefullypoured onto ice water (100 ml) and extracted with diethyl ether (100ml). The extract was washed with saturated aqueous sodium hydrogencarbonate solution (100 ml), dried (MgSO₄) and concentrated in vacuo togive the crude product. This was purified by silica (20 g) columnchromatography eluting with hexane:ethyl acetate (4:1) to give the titlecompound as a colourless oil (1.3 g, 61%).

[1105] NMR (CDCl₃) 0.8-1.4 (m, 6H), 1.6-1.8 (m, 4H), 2.0 (m, 1H), 3.95(d, 2H), 5.6-5.8 (m, 2H).

[1106] MS (thermospray): M/Z [MH⁺] 203.3; C₉H₁₅ ⁷⁹Br+H requires 203.0.

[1107] Preparation 89

[1108] A solution of 4-bromobenzenesulfonyl chloride (5.5 g, 21.7 mmol)dissolved in dichloromethane (15 ml) was added dropwise to a solution of2-benzyloxyethanol (3.0 g, 19.7 mmol) in triethylamine (3 g, 29.6 mmol)at 0° C. under nitrogen. The resultant mixture was stirred for 16 h atroom temperature. To the reaction mixture was added water (3 ml) andthen the combined mixture was poured onto water (100 ml) and the productwas extracted with dichloromethane. The organic layer was washedrepeatedly with water and then saturated aqueous sodium hydrogencarbonate solution, before drying (NaSO₄) and concentrating in vacuo togive the title compound as a white solid (6.9 g, 94%).

[1109] NMR (CDCl₃): 3.65 (m, 2H), 4.2 (m, 2H), 4.45 (s, 2H), 7.2 (m,2H), 7.25-7.35 (m, 3H), 7.6 (d, 2H), 7.8 (d, 2H).

[1110] Preparation 90

[1111] To a solution of (benzyloxy)ethyl 4-bromobenzenesulfonate(Preparation 89, 6.92 g, 19.5 mmol) in acetone (60 ml) was added sodiumiodide (5.84 g, 39.0 mmol) and the reaction mixture was left to stir atroom temperature for 16 h. The resulting precipitate was filtered andthe filtrate was concentrated in vacuo. The crude residue was dissolvedin dichloromethane and washed with aqueous sodium thiosulphate solutionand then with water (2×60 ml). The organic layer was dried (Na₂SO₄) andconcentrated in vacuo to give the title compound as a pale brown oil(4.5 g, 88%).

[1112] NMR (CDCl₃): 3.25 (t, 2H), 3.75 (t, 2H), 4.6 (s, 2H).

[1113] Preparation 91

[1114] To a solution of (S)-3-cyclohexyl-3-hydroxypropyl4-bromobenzenesulfonate (J. A. Werner et al, J. Org. Chem., 1996, 61,587), (40 mg, 0.106 mmol) in dichloromethane (3 ml) was added silica (50mg) and pyridinium chlorochromate (20 mg, 0.09 mmol), and the reactionmixture was left to stir at room temperature for 16 h. The reactionmixture was subjected to direct silica (5 g) column chromatographyeluting with dichloromethane:hexane (4:1) to afford the title compoundas a yellow solid (38 mg, 96%).

[1115] NMR (CDCl₃): 1.1-1.9 (m, 10H), 2.3 (m, 1H), 2.85 (m, 2H), 4.3 (m,2H), 7.7-7.85 (m, 4H).

[1116] Preparation 92

[1117] To a solution of 1-adamantylethanol (5.8 g, 32 mmol) intriethylamine (6.7 ml) and dichloromethane (50 ml) was added4-bromobenzenesulphonyl chloride (8.9 g, 35 mmol) at room temperature.The solution was stirred for 16 h, diluted with aqueous hydrochloricacid (2M, 100 ml) and extracted with dichloromethane (100 ml). Theextract was washed with saturated aqueous sodium hydrogen carbonatesolution (100 ml) and brine (100 ml), dried (MgSO₄), and concentrated invacuo to give the title compound as a white crystalline solid (11.2 g,88%).

[1118] NMR (CDCl₃): 1.4-1.6 (m, 11H), 1.65 (d, 3H), 2.0 (2, 3H), 4.1 (t,2H), 7.6-7.8 (m, 4H).

[1119] MS (thermospray): M/Z [MH⁺] 416.3; C₁₈H₂₃ ⁷⁹BrO₃S+NH₄ requires416.1.

[1120] Preparation 93

[1121] To a solution of 2-adamantylethyl 4-bromobenzenesulfonate(Preparation 92, 1.0 g, 2.5 mmol) in acetone (25 ml) was added sodiumiodide (0.75 g, 5 mmol) and the reaction mixture was left to stir atroom temperature for 72 h. The resulting precipitate was filtered andthe filtrate was diluted with water (100 ml) and extracted withdichloromethane (100 ml). The extract was washed with brine (100 ml),dried (MgSO₄) and concentrated in vacuo to give the title compound as awhite crystalline solid (0.54 g, 75%).

[1122] NMR (CDCl₃): 1.4-1.8 (m, 15H), 1.95 (t, 2H), 3.1 (t, 2H).

[1123] Preparation 94

[1124] To a solution of methyl6-(3-aminophenyl)-3-hexyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate(Preparation 95, 25 mg, 0.0726 mmol) in anyhydrous tetrahydrofuran (1ml) at −10° C. under nitrogen was added lithium aluminium hydride (1Msolution in tetrahydrofuran, 218 μl, 0.218 mmol) dropwise over 10 min.The reaction was left to warm to room temperature then heated underreflux for 18 h. The cooled reaction was poured into hydrochloric acid(2M, 5 ml) then basified with aqueous sodium hydroxide (2M, 10 ml). Themixture was extracted with ethyl acetate (2×25 ml) and the organiclayers washed with brine (25 ml), combined then dried (MgSO₄). Theorganic extracts were concentrated in vacuo then chromatographed onMerck 230-400 silica gel (7 g) eluting with ethyl acetate:2M ammonia inethanol (197:3) to give the desired product as a colourless oil (15 mg,71%).

[1125] NMR (CDCl₃, selected data for the free base): 0.90 (m, 3H),1.20-1.40 (m, 6H), 1.50 (m, 2H), 1.85 (br s, 2H), 2.50 (t, 2H), 2.60 (brd, 2H), 3.40 (d, 2H), 4.10 (s, 2H), 6.50 (d, 1H), 6.60 (br s, 1H), 6.65(d, 1H), 7.05 (dd, 1H).

[1126] MS (Thermospray): M/Z (MH⁺) 289.1; C₁₈H₂₈N₂O+H requires 289.4

[1127] Preparation 95

[1128] To a solution of methyl3-hexyl-6-(3-nitrophenyl)-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate(Preparation 96, 50 mg, 0.134 mmol) in ethanol (4.3 ml) and water (0.8ml) was added iron powder (68 mg, 1.21 mmol) then calcium chloride (8mg, 0.067 mmol). The reaction was heated under reflux for 6 h, cooledthen filtered through Celite™ washing with ethyl acetate (50 ml). Thefiltrate was concentrated and the chromatographed on Merck 230-400silica gel (10 g) eluting with ethyl acetate:hexane (40:60) to give thedesired product as a pale yellow semi-solid (26 mg, 56%).

[1129] NMR (CDCl₃, selected data for the free base): 0.90 (m, 3H),1.25-1.35 (m, 6H), 1.45 (m, 2H), 2.90 (s, 2H), 3.35 (t, 2H), 3.60 (s,3H), 6.65 (br d, 1H), 6.75 (br s, 1H), 6.80 (d, 1H), 7.10 (dd, 1H).

[1130] MS (Thermospray): M/Z (MH⁺) 345.1; C₁₉H₂₄N₂O₄+H requires 345.4

[1131] Preparation 96

[1132] To a stirred solution of 1-hexyl-1H-pyrrole-2,5-dione(Preparation 56, 123 mg, 0.678 mmol) in 1,4-dioxane (2 ml) undernitrogen was added methyl 2-diazo-2-(3-nitrophenyl)acetate (Preparation97, 100 mg, 0.452 mmol) and the reaction mixture was heated under refluxfor 48 h. The cooled mixture was concentrated in vacuo and the residuechromatographed on Merck 230-400 silica gel (20 g) eluting with ethylacetate:hexane (15:85 and then 30:70) to give a mixture of two isomericcyclopropanes (140 mg). These were separated by preparative HPLC(Condition 2), which gave in order of elution the endo isomer as a whitesolid (30 mg, 12%) some mixed fractions (40 mg, 16%) followed by the exoisomer as a white solid (60 mg, 24%).

[1133] NMR (CDCl₃, selected data for the free base endo isomer): 0.50(tt, 2H), 0.80 (t, 3H), 0.85-1.15 (m, 6H), 2.90 (t, 2H), 3.30 (s, 2H),3.70 (s, 3H), 7.50 (dd, 1H), 7.65 (d, 1H), 8.20 (br s, 2H).

[1134] MS (electrospray): M/Z (MH⁺) 375; C₁₉H₂₂N₂O₆+H requires 375

[1135] NMR (CDCl₃, selected data for the free base exo isomer): 0.90 (m,3H), 1.25-1.35 (m, 6H), 1.50 (m, 2H), 3.00 (s, 2H), 3.40 (t, 2H), 3.70(s, 3H), 7.60 (dd, 1H), 7.80 (d, 1H), 8.20 (br d, 1H), 8.30 (br s, 1H).

[1136] MS (Electrospray): M/Z (MH⁺) 375; C₁₉H₂₂N₂O₆+H requires 375

[1137] Preparation 97

[1138] To a solution of methyl 2-(3-nitrophenyl)acetate (C. Abell et al,J. Chem. Soc., Perkin Trans. 1, 1994, 1997; 3.13 g, 16.0 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (7.18 ml, 7.31 g, 48.0 mmol) inanhydrous acetonitrile (35 ml), was added a solution of4-acetamidobenzenesulphonyl azide (4.81 g, 20.0 mmol) in anhydrousacetonitrile (5 ml) in one portion. The reaction mixture was stirred for48 h at room temperature under nitrogen before pouring into water (300ml). The resultant precipitate was collected by filtration and washedwith water (50 ml) and cold methanol (50 ml) to give the desired productas an orange/yellow solid (2.60 g, 74%).

[1139] NMR (CDCl₃, selected data for the free base): 3.90 (s, 3H), 7.60(dd, 1H), 7.85 (br d, 1H), 8.00 (br d, 1H), 8.40 (br s, 1H).

[1140] Preparation 98

[1141] To a solution of[3-hexyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl methylether (Preparation 99, 16 mg, 0.048 mmol) in ethanol (1.5 ml) and water(0.3 ml) was added iron powder (25 mg, 0.435 mmol) then calcium chloride(3 mg, 0.24 mmol). The reaction mixture was heated under reflux for 6hours, cooled then filtered through Celite™ washing with ethyl acetate.The filtrate was concentrated in vacuo and chromatographed on Merck230-400 mesh silica gel (7 g) eluting with ethyl acetate:hexane:2Mammonia in hexane (50:49:1 and then 99:0:1) to give the desired productas a pale yellow oil (11 mg, 76%).

[1142] NMR (CDCl₃, selected data for the free base): 0.90 (m, 3H),1.20-1.50 (m, 8H), 1.85 (br s, 2H), 2.45 (t, 2H), 2.70 (br d, 2H), 3.20(d, 2H), 3.30 (s, 3H), 4.05 (s, 2H), 6.50 (br d, 1H), 6.70 (br s, 1H),6.75 (d, 1H), 7.05 (dd, 1H).

[1143] MS (Thermospray): M/Z (MH⁺) 303; C₁₉H₃₀N₂O+H requires 303

[1144] Preparation 99

[1145] To sodium hydride (60% oil dispersion washed with anhydrouspentane, 13 mg, 0.320 mmol) under nitrogen was added a solution of[3-hexyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hex-6-yl]methanol(Preparation 100, 51 mg, 0.160 mmol) in anhydrous tetrahydrofuran (1 ml)dropwise over 10 minutes. The reaction was stirred for 1 h at roomtemperature, cooled in an ice-water bath and dimethylsulphate (18 μl, 24mg, 0.192 mmol) added. The reaction mixture was allowed to warm to roomtemperature slowly and then stirred at room temperature for 16 h, beforequenching by dropwise addition of water (5 ml). The reaction mixture waspartitioned between ethyl acetate (25 ml) and sodium carbonate (25 ml).The separated aqueous layer was extracted with ethyl acetate (25 ml) andthe organic extracts were washed with brine (25 ml). The combinedorganic extracts were dried (MgSO₄) and then concentrated in vacuo. Theresidue was chromatographed on Merck 230-400 mesh silica gel elutingwith ethyl acetate hexane:2M ammonia in ethanol (20:79:1 and then40:49:1) to give the desired product as a pale yellow oil (16 mg, 30%).

[1146] NMR (CDCl₃, selected data for the free base): 0.90 (m, 3H),1.25-1.45 (m, 8H), 1.90 (br s, 2H), 2.45 (t, 2H), 2.70 (br d, 2H), 3.20(d, 2H), 3.30 (s, 3H), 4.15 (s, 2H), 7.40 (dd, 1H), 7.65 (d, 1H), 8.05(br d, 1H), 8.15 (br s, 1H).

[1147] MS (thermospray): M/Z (MH⁺) 333; C₁₉H₂₈N₂O₃+H requires 333

[1148] Preparation 100

[1149] To a solution of methyl3-hexyl-6-(3-nitrophenyl)-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate(Preparation 96, 200 mg, 0.534 mmol) in anhydrous tetrahydrofuran (1 ml)cooled in an ice-water bath under nitrogen was added borane (1M solutionin tetrahydrofuran, 2.14 ml, 2.14 mmol) dropwise over 30 minutes. Thereaction mixture was allowed to warm to room temperature and was thenheated under reflux for 1 h. The mixture was quenched by the carefuladdition of methanol and was then heated under reflux for 16 h. Thereaction was cooled and the solvent removed in vacuo. More methanol wasadded and the mixture heated under reflux for 16 h. The solvent wasagain removed in vacuo and this process was repeated twice more. Theresidue was chromatographed on Merck 230-400 mesh silica gel (25 g)eluting with ethyl acetate:hexane:2M ammonia in ethanol (40:59:1) togive the desired product as a pale yellow solid (113 mg, 66%).

[1150] NMR (CDCl₃, selected data for the free base): 0.90 (m, 3H),1.20-1.40 (m, 6H), 1.50 (m, 2H), 1.90 (br s, 2H), 2.50 (t, 2H), 2.65 (brd, 2H), 3.45 (d, 2H), 4.20 (s, 2H), 7.45 (dd, 1H), 7.65 (d, 1H), 8.05(br d, 1H), 8.15 (br s, 1H).

[1151] MS (thermospray): M/Z (MH⁺) 319; C₁₈H₂₆N₂O₃+H requires 319

[1152] Preparation 101

[1153]3-Hexyl-6-(3-aminophenyl)-6-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexane-2,4-dione(Preparation 102, 170 mg, 0.46 mmol) was dissolved in anhydroustetrahydrofuran (5 ml) in a dry, nitrogen-flushed flask fitted with athermometer and reflux condenser. The pale orange solution was cooled to−12° C. in an ice/methanol bath and lithium aluminium hydride (1Msolution in tetrahydrofuran, 0.9 ml, 0.9 mmol) was added dropwisemaintaining the internal temperature below −10° C. Once the addition wascompleted, the red-orange mixture was allowed to warm to roomtemperature before heating under reflux for 1.5 h. The mixture wascooled to room temperature and the residual lithium aluminium hydridequenched by the careful addition of aqueous hydrochloric acid (2M) untilhydrogen evolution had ceased. The mixture was then neutralised withsaturated sodium hydrogen carbonate solution and extracted with ethylacetate (2×20 ml). The combined organic extracts were washed with brine(10 ml), dried (MgSO₄), filtered and the solvents removed in vacuo togive the product as a pale brown gum (145 mg, 93%).

[1154] NMR (CDCl₃, selected data for the free base): 0.80-0.95 (m, 3H),1.20-1.45 (m, 8H), 1.45-1.60 (m, 2H), 2.40 (t, 2H), 2.60 (d, 2H), 3.10(q, 2H), 3.20 (d, 2H), 3.60 (br, 2H), 6.50 (d, 1H), 6.60 (s, 1H), 6.65(d, 1H), 7.05 (t, 1H).

[1155] MS (electrospray): M/Z (MH⁺) 341.4; C₁₉H₂₇F₃N₂+H requires 341.4.

[1156] Preparation 102

[1157]3-Hexyl-6-(3-nitrophenyl)-6-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexane-2,4-dione(Preparation 103, 178 mg, 0.45 mmol) was dissolved in ethanol (15 ml).Iron powder (225 mg, 4.0 mmol) was added at room temperature followed bycalcium chloride (50 mg, 0.45 mmol), dissolved in water (2 ml). Thevigorously stirred mixture was heated under reflux for 2 h then cooledto room temperature and filtered through a pad of silica. The solventwas removed in vacuo and the filtrate was dissolved in dichloromethaneand filtered through a Whatman anotop 10 plus™ cartridge. The organicmixture was concentrated in vacuo to give the product as a brown gum(170 mg, 100%).

[1158] NMR (CDCl₃, selected data for the free base): 0.80-0.95 (m, 3H),1.20-1.35 (m, 6H), 1.45-1,60 (m, 2H), 2.55 (q, 2H), 2.80 (s, 2H), 3.45(t, 2H), 2.75 (broad s, 2H), 6.55 (d, 1H), 6.65 (s, 1H), 6.70 (d, 1H),7.10 (t, 1H).

[1159] MS (thermospray): M/Z (MNH₄ ⁺) 386.5; C₁₉H₂₃F₃N₂O₂+NH₄ requires386.4

[1160] Preparation 103

[1161] 3,3,3-Trifluoro-1-(3-nitrophenyl)-1-propanone hydrazone(Preparation 104, 150 mg, 0.6 mmol) was dissolved in dioxan (10 ml) andmanganese dioxide (600 mg, 7.1 mmol) was added in one portion at roomtemperature. After stirring for 30 min, the reaction mixture wasfiltered through a pad of Arbocel™ directly into a flask containing astirred solution of 1-hexyl-1H-pyrrole-2,5-dione (Preparation 56, 44 mg,0.2 mmol) in dioxan (10 ml). The filter pad was washed further withdioxan (40 ml), and was also added to the reaction mixture. Theresulting amber-yellow solution was stirred for 16 h at roomtemperature. The colourless mixture was then heated under reflux for 1 hbefore cooling to room temperature and concentrating in vacuo. Theresidue was purified by chromatography on silica gel (10 g), elutingwith hexane:ether (2:1) to give the product as a white solid (178 mg,74%).

[1162] NMR (selected data): 0.85-0.95 (m, 3H), 1.25-1.35 (m, 6H),1.50-1.65 (m, 2H), 2.60 (q, 2H), 2.90 (s, 2H), 3.40-3.55 (t, 2H), 7.60(t, 1H), 7.75 (d, 1H), 8.20 (d, 1H), 8.30 (s, 1H).

[1163] MS (APCI): M/Z (M−H⁺) 397.0: C₁₉H₂₁F₃N₂O₄−H requires 397.4.

[1164] Preparation 104

[1165] 3,3,3-Trifluoro-1-(3-nitrophenyl)-1-propanone (Sov. Prog. Chem.(Engl.Transl.), 1966, 32, 745, 1.8 g, 7.72 mmol) was dissolved intetrahydrofuran (10 ml) and hydrazine monohydrate (0.56 ml, 11.58 mmol)was added dropwise at room temperature. The reaction mixture was stirredfor 1 h at room temperature then heated under reflux for 40 min. Thereaction mixture was concentrated in vacuo and the residue treated withwater (10 ml) and extracted with dichloromethane (4×10 ml). The organicextracts were concentrated in vacuo and the residue was purified bychromatography on silica gel (100 g), eluting withdichloromethane:hexane (1:1 and then 2:1). The product was obtained asan amber gum (159 mg, 8%).

[1166] NMR (CDCl₃, selected data for the free base): 3.55 (q, 2H), 5.95(br s, 2H), 7.55 (t, 1H), 8.00 (d, 1H), 8.15 (d, 1H), 8.55 (s, 1H).

[1167] MS (electrospray): M/Z (M−H⁺) 246.1 C₉H₈F₃N₃O₂−H requires 246.2.

[1168] Preparation 105

[1169] To a solution of3-hexyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile(Preparation 106, 3 mg, 0.0096 mmol) in ethanol (1 ml) and water (0.2ml) was added iron powder (6 mg, 0.096 mmol) then calcium chloride (0.6mg, 0.0048 mmol). The reaction was heated under reflux for 6 h, cooledthen filtered through Celite™ washing with ethyl acetate (50 ml). Thefiltrate was concentrated in vacuo to give the desired product as a paleyellow oil (1.7 mg, 63%).

[1170] NMR (CDCl₃, selected data for the free base): 0.90 (m, 3H),1.25-1.35 (m, 6H), 1.45 (m, 2H), 2.20 (m, 2H), 2.45 (m, 2H), 2.85 (m,2H), 3.20 (m, 2H), 6.50-6.60 (m, 2H), 6.70 (br s, 1H), 7.10 (dd, 1H).

[1171] MS (thermospray): M/Z (M⁺) 283.2; C₁₈H₂₅N₃ requires 283.2

[1172] Preparation 106

[1173] A solution of3-hexyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-6-carbaldehyde(Preparation 107, 9 mg, 0.028 mmol) and diphenylsulphilimine monohydrate(12.5 mg, 0.057 mmol) in anhydrous benzene (1 ml) was heated underreflux under nitrogen for 24 hours. The solvent was removed in vacuo andthe residue chromatographed on Merck 230-400 mesh silica gel (5 g)eluting with ethyl acetate:hexane (30:70 and then 50:50) to give thedesired product as a pale yellow oil (3 mg, 34%).

[1174] NMR (CDCl₃, selected data for the free base): 0.90 (m, 3H),1.20-1.45 (m, 6H), 1.50 (m, 2H), 2.25 (m, 2H), 2.55 (m, 2H), 2.80 (m,2H), 3.35 (m, 2H), 7.5 (dd, 1H), 7.80 (d, 1H), 8.05 (br s, 1H), 8.15 (brd, 1H).

[1175] MS (thermospray): M/Z (MH⁺) 314.2; C₁₈H₂₃N₃O₂+H requires 314.2

[1176] Preparation 107

[1177] To a solution of[3-hexyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hex-6-yl]methanol(Preparation 100, 50 mg, 0.157 mmol) in anhydrous dimethylsulphoxide (1ml) was added anhydrous triethylamine (131 μl, 0.941 mmol) followed by asolution of sulphur trioxide-pyridine complex (75 mg, 0.471 mmol) inanhydrous dimethyl sulphoxide (0.7 ml). The reaction mixture was stirredat room temperature for 40 h under nitrogen, before pouring intodichloromethane (25 ml) and basifying with aqueous saturated sodiumbicarbonate solution (20 ml). The separated aqueous layer was extractedwith dichloromethane (20 ml) and the combined organic extracts weredried (MgSO₄) and then concentrated in vacuo to give the desired productas a pale yellow oil (9 mg, 18%).

[1178] NMR (CDCl₃, selected data for the free base): 0.90 (m, 3H),1.20-1.40 (m, 6H), 1.50 (m, 2H), 2.05 (br s, 2H), 2.55-2.60 (m, 4H),3.15 (d, 2H), 7.45 (dd, 1H), 7.70 (d, 1H), 8.05 (br d, 1H), 8.15 (br s,1H), 9.40 (s, 1H).

[1179] Preparation 108

[1180] To a solution ofN-{3-hexyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl}acetamide(Preparation 109, 84 mg, 0.234 mmol) in ethanol (4 ml) and water (1 ml)was added iron powder (120 mg, 2.15 mmol) and calcium chloride (16 mg,0.14 mmol). The mixture was stirred and heated under reflux for 1¼ h,before allowing to cool and filtering through Celite™, washing with hotethanol. The filtrate was concentrated in vacuo to give a brown residuewhich was partitioned between dichloromethane (5 ml) and water (5 ml),leaving some insoluble material at the interface. The phases wereseparated and the aqueous layer was re-extracted with dichloromethane(2×5 ml). The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo to give the title compound as a golden oil (68 mg,77%).

[1181] NMR (CDCl₃): 0.90 (m, 3H), 1.23-1.40 (m, 6H), 1.45 (m, 2H),1.80-1.90 (m, 5H), 2.50 (m, 2H), 2.80 (m, 2H), 3.10 (m, 2H), 3.65 (m,2H), 3.95 (m, 2H), 5.45 (m, 1H), 6.5 (m, 1H), 6.55-6.65 (m, 2H), 7.05(t, 1H).

[1182] MS (thermospray): M/Z (MH⁺) 330.3; C₂₀H₃₁N₃O+H requires 330.3.

[1183] Preparation 109

[1184] A solution of[3-hexyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hex-6-yl]methylamine(Preparation 110, 80 mg, 0.234 mmol) and triethylamine (0.16 ml, 0.35mmol) in anhydrous dichloromethane (2 ml) was stirred under nitrogen andtreated with acetyl chloride (0.025 ml, 0.35 mmol) followed by4-dimethylaminopyridine (a few crystals). The reaction mixture wasstirred for 18 h at room temperature, then concentrated in vacuo to givea yellow solid (205 mg). The crude solid was purified by columnchromatography on silica gel (10 g) eluting withdichloromethane:ethanol:0.88 ammonia (300:8:1 and then 50:8:1) to givethe title compound as a yellow solid (84 mg, 100%).

[1185] NMR (CDCl₃): 0.90 (m, 3H), 1.22-1.35 (m, 6H), 1.50 (m, 2H),1.80-1.95 (m, 5H), 2.50 (m, 2H), 2.75 (m, 2H), 3.25 (m, 2H), 4.25 (m,2H), 5.55 (m, 1H), 7.45 (m, 1H), 7.65 (d, 1H), 8.00-8.10 (m, 2H).

[1186] MS (thermospray): M/Z (MH⁺) 360.2; C₂₀H₂₉N₃O₃+H requires 360.2.

[1187] Preparation 110

[1188] To a solution of3-hexyl-6-(3-nitrophenyl)-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carbonitrile(Preparation 111, 250 mg, 0.732 mmol) in anhydrous tetrahydrofuran (3ml) stirred under nitrogen was added dropwise borane-tetrahydrofarancomplex (1.0M in tetrahydrofuran, 2.9 ml, 2.9 mmol). The reactionmixture was heated at reflux for 2 h, before cooling and quenching withdry methanol (2 ml). The solution in methanol was heated under refluxfor 18 h before concentrating in vacuo. The residue was again dissolvedin methanol (ca 5 ml) and heated at reflux for 3 hours, followed byevaporation to dryness in vacuo. This process was repeated once more andextensive drying gave a brown oil (270 mg) which was purified by columnchromatography on silica gel (13 g) eluting withdichloromethane:ethanol:0.88 ammonia (150:8:1). This gave the tidecompound as an orange oil (124 mg, 53%).

[1189] NMR (CDCl₃): 0.90 (t, 3H), 1.20-1.35 (m, 6H), 1.45 (m, 2H), 1.85(m, 2H), 2.45 (t, 2H), 2.75 (m, 2H), 3.20 (m, 2H), 3.42 (s, 2H), 7.45(t, 1H), 7.65 (d, 1H), 8.05 (d, 1H), 8.17 (s, 1H).

[1190] MS (thermospray): M/Z (MH⁺) 318.2; C₂₀H₂₉N₃O₃+H requires 318.2.

[1191] Preparation 111

[1192] A solution of 2-chloro-2-(3-nitrophenyl)acetonitrile (Preparation112, 103 mg, 0.524 mmol) and 1-hexyl-1H-pyrrole-2,5-dione (Preparation56, 79 mg, 0.436 mmol) in N,N-dimethylformamide (2 ml) was addeddropwise over 30 min to a stirred slurry of potassium carbonate (120 mg,0.868 mmol) and sodium iodide (33 mg, 0.22 mmol) inN,N-dimethylformamide (4 ml) and water (0.1 ml) at 0° C. The reactionmixture was stirred for 30 min at 0° C. and then allowed to warm to roomtemperature. After stirring at room temperature for 2 h the mixture wasdiluted with water (10 ml) and extracted with ethyl acetate (3×5 ml).The combined organic phases were dried (MgSO₄) and concentrated in vacuoto give a residue which was purified by column chromatography on silicagel eluting with hexane:ethyl acetate (5:1 and then 3:1). This gave thetitle compound as brown needles (47 mg, 32%).

[1193] NMR (CDCl₃): 0.90 (m, 3H), 1.20-1.40 (m, 6H), 1.63 (m, 2H), 3.21(s, 2H), 3.56 (m, 2H), 7.68 (t, 1H), 7.80 (m, 1H), 8.12 (s, 1H), 8.30(d, 1H).

[1194] Preparation 112

[1195] A solution of 2-hydroxy-2-(3-nitrophenyl)acetonitrile(Preparation 113, 1.0 g, 5.62 mmol) in diethyl ether (10 ml) was stirredat room temperature and treated with pyridine (0.1 ml, 1.24 mmol)followed by thionyl chloride (0.82 ml, 11.2 mmol) dropwise over 5minutes. The mixture was gently heated under reflux and after 30 min thesolvent was removed by evaporation to give a pale yellow solid. This waspurified by column chromatography on silica gel eluting withhexane:ethyl acetate (3:1 and then 2:1) to give the title compound as awhite crystalline solid (980 mg, 89%).

[1196] NMR (CDCl₃): 5.68 (s, 1H), 7.70 (t, 1H), 7.95 (d, 1H), 8.35 (d,1H), 8.42 (s, 1H).

[1197] MS (electrospray): M/Z (M⁺) 195.6; C₈H₅ClN₂O₂ requires 196.0.

[1198] Preparation 113

[1199] To a stirred solution of 3-nitrobenzaldehyde (5.0 g, 33. mmol) indichloromethane (30 ml) at 0° C. was added trimethylsilyl cyanide (4.63ml, 34.7 mmol). After stirring for 6 h at room temperature, zinc iodide(210 mg, 0.66 mmol) was added which caused the reaction mixture to warmand gently reflux. After 30 min, the reaction mixture was treated withhydrochloric acid (2M, 100 ml) and diethyl ether (150 ml) and stirredvigorously for 16 h. The phases were separated and the aqueous phase wasfurther extracted with diethyl ether (3×100 ml). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo to give a residuewhich was purified by column chromatography on silica gel eluting withhexane:ethyl acetate (3:1 and then 1:1). This gave the title compound asa clear oil (5.0 g, 85%).

[1200] NMR (CDCl₃): 3.42 (br s, 1H), 5.70 (s, 1H), 7.65 (t, 1H), 7.92(d, 1H), 8.32 (m, 1H), 8.42 (s, 1H).

[1201] MS (electrospray): M/Z (M−H⁺) 177.0; C₈H₆N₂O₃−H requires 177.0.

[1202] Preparation 114

[1203] To a solution of 4-(trifluoromethyl)phenyl acetic acid (63 mg,0.31 mmol) in N,N-dimethylformamide (6.5 ml) was added1-hydroxybenzotriazole monohydrate (50 mg, 0.33 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (85 mg, 0.44mmol). After stirring at room temperature for 5 min the mixture wastreated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 100 mg, 0.33 mmol) and sodium hydrogen carbonate (28mg, 0.34 mmol). The reaction mixture was stirred at room temperature for18 h before concentrating in vacuo. Water (10 ml) was added and thereaction mixture was extracted with ethyl acetate (2×15 ml). Thecombined organic extracts were dried (Na₂SO₄), filtered and concentratedin vacuo to give a light brown oil. The residue was purified bychromatography using a Sep-Pak™ cartridge packed with silica gel (5 g)eluting with dichloromethane:ethanol:0.88 ammonia (200:8:1) to affordthe title compound as a glassy oil (70 mg, 47%).

[1204] NMR (CDCl₃): 1.15 (s, 3H), 1.95 (m, 2H), 3.00 (s, 3H), 3.55-3.90(m, 6H), 6.45 (br. s, 1H), 7.00-7.15 (m, 3H), 7.25 (m, 1H), 7.40 (d,2H), 7.60 (d, 2H).

[1205] MS (thermospray): M/Z (MH⁺) 452.8; C₂₂H₂₃F₃N₂O₃S+H requires453.1.

[1206] Preparation 115

[1207] To a solution of 2-indane carboxylic acid (E. D. Bergmann and E.Hoffmann, J. Org. Chem., 1961, 26, 3555, 100 mg, 0.62 mmol) inN,N-dimethylformamide (13 ml) was added 1-hydroxybenzotriazolemonohydrate (100 mg, 0.66 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (170 mg,0.88 mmol). After stirring at room temperature for 5 min the mixture wastreated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 200 mg, 0.66 mmol) and triethylamine (133 mg, 1.32mmol). The reaction mixture was stirred at room temperature for 72 hbefore concentrating in vacuo. Water (10 ml) was added and the reactionmixture was extracted with ethyl acetate (2×15 ml). The combined organicextracts were washed with water (10 ml) and saturated brine (10 ml),dried (Na₂SO₄), filtered and concentrated in vacuo to give a light brownoil. The residue was purified by chromatography using a Sep-Pak™cartridge packed with silica gel (10 g) eluting withdichloromethane:ethanol:0.88 ammonia (300:8:1) to afford the titlecompound as a white foam (117 mg, 43%).

[1208] NMR (CDCl₃, selected data): 1.30 (s, 3H), 2.00 (m, 2H), 3.00 (s,3H), 3.05-3.45 (m, 5H), 3.70-3.80 (m, 3H), 3.95 (m, 1H), 6.50 (br., 1H),7.00-7.35 (m, 8H).

[1209] MS (thermospray): M/Z (MH⁺) 411.2; C₂₃H₂₆N₂O₃S+H requires 411.2.

[1210] Preparation 116

[1211] To a solution of 2-(1-benzothiophen-3-yl)acetic acid (118 mg,0.62 mmol) in N,N-dimethylformamide (13 ml) was added1-hydroxybenzotriazole monohydrate (100 mg, 0.66 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (170 mg,0.88 mmol). After stirring at room temperature for 5 min the mixture wastreated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 200 mg, 0.66 mmol) and triethylamine (133 mg, 1.32mmol). The reaction mixture was stirred at room temperature for 72 hbefore concentrating in vacuo. Water (10 ml) was added and the reactionmixture was extracted with ethyl acetate (2×15 ml). The combined organicextracts were washed with water (10 ml) and saturated brine (10 ml),dried (Na₂SO₄), filtered and concentrated in vacuo to give a light brownoil. The residue was purified by chromatography using a Sep-Pak™cartridge packed with silica gel (10 g) eluting withdichloromethane:ethanol:0.88 ammonia (300:8:1) to afford the titlecompound as a white foam (99 mg, 34%).

[1212] NMR (CDCl₃) 1.15 (s, 3H), 1.95 (m, 2H), 3.00 (s, 3H), 3.60 (d,1H), 3.75-3.90 (m, 5H), 6.5 (br., 1H), 7.00-7.10 (m, 3H), 7.20-7.35 (m,2H), 7.35-7.45 (m, 2H), 7.85 (m, 2H).

[1213] MS (thermospray): M/Z (MH⁺) 441.1; C₂₃H₂₄N₂O₃S₂+H requires 441.1.

[1214] Preparation 117

[1215] To a solution of 2-(1-methyl-1H-indol-3-yl)acetic acid (117 mg,0.62 mmol) in N,N-dimethylformamide (13 ml) was added1-hydroxybenzotriazole monohydrate (100 mg, 0.66 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloridehydrochloride (170 mg, 0.88 mmol). After stirring at room temperaturefor 5 min the mixture was treated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 200 mg, 0.66 mmol) and triethylamine (133 mg, 1.32mmol). The reaction mixture was stirred at room temperature for 72 hbefore concentrating in vacuo. Water (10 ml) was added and the reactionmixture was extracted with ethyl acetate (2×15 ml). The combined organicextracts were washed with water (10 ml) and saturated brine (10 ml),dried (Na₂SO₄), filtered and concentrated in vacuo to give a light brownoil. The residue was purified by chromatography using a Sep-Pak™cartridge packed with silica gel (10 g) eluting withdichloromethane:ethanol:0.88 ammonia (300:8:1) to afford the titlecompound as a white foam (58 mg, 20%).

[1216] NMR (CDCl₃, selected data): 1.15 (s, 3H), 1.90 (br. s, 2H), 3.00(s, 3H), 3.60-3.90 (m, 9H), 6.55 (br., 1H), 7.00-7.35 (m, 8H), 7.60 (d,1H).

[1217] MS (thermospray): M/Z (MH⁺) 438.2; C₂₄H₂₇N₃O₃S+H requires 438.2

[1218] Preparation 118

[1219] To a solution of 3-(4-fluorophenyl)propanoic acid (104 mg, 0.62mmol) in N,N-dimethylformamide (13 ml) was added 1-hydroxybenzotriazolemonohydrate (100 mg, 0.66 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloridehydrochloride (170 mg, 0.88 mmol). After stirring at room temperaturefor 5 min the mixture was treated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 200 mg, 0.66 mmol) and triethylamine (133 mg, 1.32mmol). The reaction mixture was stirred at room temperature for 72 hbefore concentrating in vacuo. Water (10 ml) was added and the reactionmixture was extracted with ethyl acetate (2×15 ml). The combined organicextracts were washed with water (10 ml) and saturated brine (10 ml),dried (Na₂SO₄), filtered and concentrated in vacuo to give a light brownoil. The residue was purified by chromatography using a Sep-Pak™cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol:0.88 ammonia (300:8:1) to afford the title compound as a whitefoam (100 mg, 36%).

[1220] NMR (CDCl₃): 1.15 (s, 3H), 1.95 (m, 2H), 2.55 (m, 2H), 2.95 (m,2H), 3.00 (s, 3H), 3.50 (d, 1H), 3.60-3.80 (m, 3H), 6.55 (br., 1H),6.90-7.30 (m, 8H)

[1221] MS (thermospray): M/Z (MH⁺) 417.3; C₂₂H₂₅FN₂O₃S+H requires 417.2.

[1222] Preparation 119

[1223] To a solution of 3-(3,4-dichlorophenyl)propanoic acid (35 mg,0.16 mmol) in N,N-dimethylformamide (4 ml) was added1-hydroxybenzotriazole monohydrate (26 mg, 0.17 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44 mg, 0.23mmol). After stirring at room temperature for 5 min the mixture wastreated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 52 mg, 0.17 mmol) and triethylamine (33 mg, 0.33 mmol).The reaction mixture was stirred at room temperature for 72 h beforeconcentrating in vacuo. Water (10 ml) was added and the reaction mixturewas extracted with ethyl acetate (2×15 ml). The combined organicextracts were washed with water (10 ml) and saturated brine (10 ml),dried (Na₂SO₄), filtered and concentrated in vacuo to give a light brownoil. The residue was purified by chromatography using a Sep-Pak™cartridge packed with silica gel (10 g) eluting withdichloromethane:ethanol:0.88 ammonia (300:8:1) to afford the titlecompound as a white foam (38 mg, 51%).

[1224] NMR (CDCl₃): 1.20 (s, 3H), 1.95 (m, 2H), 2.55 (m, 2H), 2.95 (m,2H), 3.00 (s, 3H), 3.50 (m, 1H), 3.70-3.80 (m, 3H), 6.50 (br., 1H),7.00-7.15 (m, 4H), 7.20-7.40 (m, 3H).

[1225] MS (thermospray): M/Z (MH⁺) 466.8; C₂₂H₂₄Cl₂N₂O₃S+H requires467.1.

[1226] Preparation 120

[1227] To a solution of 3-(1,3-benzodioxol-5-yl)propanoic acid (120 mg,0.62 mmol) in N,N-dimethylformamide (13 ml) was added1-hydroxybenzotriazole monohydrate (100 mg, 0.66 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (170 mg,0.88 mmol). After stirring at room temperature for 5 min the mixture wastreated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 200 mg, 0.66 mmol) and triethylamine (133 mg, 1.32mmol). The reaction mixture was stirred at room temperature for 72 hbefore concentrating in vacuo. Water (10 ml) was added and the reactionmixture was extracted with ethyl acetate (2×15 ml). The combined organicextracts were washed with water (10 ml) and saturated brine (10 ml),dried (Na₂SO₄), filtered and concentrated in vacuo to give a light brownoil. The residue was purified by chromatography using a Sep-Pak™cartridge packed with silica gel (10 g) eluting withdichloromethane:ethanol:0.88 ammonia (300:8:1) to afford the titlecompound as a white foam (107 mg, 38%).

[1228] NMR (CDCl₃): 1.20 (s, 3H), 1.95 (br., 2H), 2.55 (m, 2H), 2.95 (m,2H), 3.00 (s, 3H), 3.50 (m, 1H), 3.65-3.80 (m, 3H), 5.90 (s, 2H), 6.55(br., 1H), 6.65-6.75 (m, 3H), 7.00-7.15 (m, 3H), 7.15-7.20 (m, 1H).

[1229] MS (thermospray): M/Z (MH⁺) 443.2; C₂₃H₂₆N₂O₅S+H requires 443.2.

[1230] Preparation 121

[1231] To a solution of 2-(5-chloro-3-thienyl)acetic acid (T. L. Cairnsand B. C. McKusick, J. Org. Chem., 1950, 15, 790; 109 mg, 0.62 mmol) inN,N-dimethylformamide (13 ml) was added 1-hydroxybenzotriazolemonohydrate (100 mg, 0.66 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (170 mg,0.88 mmol). After stirring at room temperature for 5 min the mixture wastreated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 200 mg, 0.66 mmol) and triethylamine (133 mg, 1.32mmol). The reaction mixture was stirred at room temperature for 72 hbefore concentrating in vacuo. Water (10 ml) was added and the reactionmixture was extracted with ethyl acetate (2×15 ml). The combined organicextracts were washed with water (10 ml) and saturated brine (10 ml),dried (Na₂SO₄), filtered and concentrated in vacuo to give a light brownoil. The residue was purified by chromatography using a Biotage Flash12™ cartridge packed with silica gel (8 g) eluting withdichloromethane:ethanol:0.88 ammonia (250:8:1) to afford a crude productwhich was further purified using a Sep-Pak™ cartridge packed with silicagel (10 g) eluting with dichloromethane: ethanol:0.88 ammonia (300:8:1)to afford the title compound as a white foam (51 mg, 19%).

[1232] NMR (CDCl₃, selected data): 1.20 (s, 3H), 2.00 (m, 2H), 3.00 (s,3H), 3.60-3.95 (m, 6H), 6.50 (br., 1H), 6.70-6.80 (m, 2H), 7.00-7.15 (m,3H), 7.25 (m, 1H).

[1233] MS (thermospray): M/Z (MH⁺) 425.2; C₁₉H₂₁ClN₂O₃S₂+H requires425.1.

[1234] Preparation 122

[1235] To a solution of 3-methyl-3-phenylbutanoic acid (F. C. Whitmore,C. A. Weisgerber and A. C. Shabica Jr., J. Am. Chem. Soc.,1943, 65,1469; 110 mg, 0.62 mmol) in N,N-dimethylformamide (13 ml) was added1-hydroxybenzotriazole monohydrate (100 mg, 0.66 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (170 mg,0.88 mmol). After stirring at room temperature for 5 min the mixture wastreated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 200 mg, 0.66 mmol) and triethylamine (133 mg, 1.32mmol). The reaction mixture was stirred at room temperature for 72 hbefore concentrating in vacuo. Water (10 ml) was added and the reactionmixture was extracted with ethyl acetate (2×15 ml). The combined organicextracts were washed with water (10 ml) and saturated brine (10 ml),dried (Na₂SO₄), filtered and concentrated in vacuo to give a light brownoil. The residue was purified by chromatography using a Biotage Flash12™ cartridge packed with silica gel (8 g) eluting with dichloromethaneethanol:0.88 ammonia (250:8:1) to afford a pale yellow oil which wasfurther purified using a Sep-Pak™ cartridge packed with silica gel (10g) eluting with dichloromethane:ethanol:0.88 ammonia (300:8:1) to affordthe tide compound as a white foam (70 mg, 26%).

[1236] NMR (CDCl₃): 1.05 (s, 3H), 1.55 (m, 6H), 1.85 (m, 2H), 2.55 (m,2H), 3.00 (s, 3H), 3.30-3.50 (m, 2H), 3.50-3.70 (m, 2H), 6.50 (br., 1H),6.95-7.10 (m, 3H), 7.10-7.50 (m, 6H).

[1237] MS (thermospray): M/Z (MH⁺) 427.4; C₂₄H₃₀N₂O₃S+H requires 427.2.

[1238] Preparation 123

[1239] To a solution of 3-(1H-indol-3-yl)propanoic acid (235 mg, 1.2mmol) in N,N-dimethylformamide (13 ml) was added 1-hydroxybenzotriazolemonohydrate (200 mg, 1.31 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (340 mg,1.77 mmol). After stirring at room temperature for 5 min the mixture wastreated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 400 mg, 1.3 mmol) and sodium hydrogen carbonate (220mg, 2.6 mmol). The reaction mixture was stirred at room temperature for72 h before concentrating in vacuo. Water (20 ml) was added and thereaction mixture was extracted with ethyl acetate (2×30 ml). Thecombined organic extracts were washed with water (20 ml) and saturatedbrine (20 ml), dried (MgSO₄), filtered and concentrated in vacuo to givea pale yellow solid. The crude product was purified by shaking withdichloromethane (10 ml) and after filtration the filtrate wasconcentrated in vacuo to afford a pale yellow solid which was furtherpurified by chromatography using a Sep-Pak™ cartridge packed with silicagel (10 g) eluting with dichloromethane:ethanol:0.88 ammonia (300:8:1)to afford the title compound as a white solid (235 mg, 43%).

[1240] NMR (CDCl₃): 1.05 (s, 3H), 1.90 (m, 2H), 2.70 (m, 2H), 3.00 (s,3H), 3.20 (m, 2H), 3.45 (m, 1H), 3.60-3.80 (m, 3H), 6.40 (br., 1H),7.00-7.30 (m, 7H), 7.37 (d, 1H), 7.60 (d, 1H), 7.95 (br., 1H).

[1241] MS (thermospray): M/Z (MH⁺) 438.1; C₂₄H₂₇N₃O₃S+H requires 438.2.

[1242] Preparation 124

[1243] To a solution of 3-(4-pyridinyl)propanoic acid (E. A. Hallinan etal., J. Med. Chem., 1996, 39, 609, 96 mg, 0.635 mmol) inN,N-dimethylformamide (6 ml) was added 1-hydroxybenzotriazolemonohydrate (96 mg, 0.627 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (122 mg,0.636 mmol). After stirring at room temperature for 5 min the mixturewas treated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 193 mg, 0.635 mmol) and sodium hydrogen carbonate (160mg, 1.907 mmol). The reaction mixture was stirred at room temperaturefor 5 d before partitioning between water (5 ml) and dichloromethane (5ml). The layers were separated and the aqueous layer was extracted withdichloromethane (2×5 ml). The combined organic extracts were dried(Na₂SO₄), filtered and concentrated in vacuo to give a brown oil (260mg). The residue was purified by chromatography using a Biotage Flash12™ cartridge packed with silica gel (8 g) eluting withdichloromethane:ethanol:0.88 ammonia (300:8:1) to afford the titlecompound as a pink foam (100 mg, 62%).

[1244] NMR (CDCl₃): 1.18 (s, 3H), 1.95 (m, 2H), 2.60 (m, 2H), 2.95-3.05(m, 4H), 3.52 (m, 2H), 3.70-3.80 (m, 4H), 7.00-7.10 (m, 2H), 7.10-7.20(m, 2H), 7.20-7.30 (m, 2H), 8.50 (d, 2H).

[1245] MS (electrospray): M/Z (MH⁺) 400.2; C₂₁H₂₅N₃O₃S+H requires 400.2.

[1246] IR ?_(max) (polyethylene card)/cm⁻¹ : 1328 (w), 1447 (w), 1606(m), 1622 (m), 2915 (m).

[1247] Preparation 125

[1248] To a solution of 3-(2-thienyl)propanoic acid (200 mg, 1.2 mmol)in N,N-dimethylformamide (25 ml) was added 1-hydroxybenzotriazolemonohydrate (200 mg, 1.31 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (340 mg,1.77 mmol). After stirring at room temperature for 10 min the mixturewas treated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 400 mg, 1.3 mmol) and sodium hydrogen carbonate (220mg, 2.6 mmol). The reaction mixture was stirred at room temperature for3 h before concentrating in vacuo. Water (15 ml) was added and thereaction mixture was extracted with ethyl acetate (1×30 ml and 2×15 ml).The combined organic extracts were washed with water (15 ml) andsaturated brine (15 ml), dried (MgSO₄), and concentrated in vacuo togive a buff solid. The crude product was sonicated in methanol (5 ml) toafford the title compound as an off-white solid (350 mg, 66%, m.p.184.5° C.).

[1249] NMR (CDCl₃, selected data): 1.20 (s, 3H), 1.95 (m, 2H), 2.60 (m,2H), 3.00 (s, 3H), 3.25 (m, 2H), 3.55 (d, 1H), 3.70-3.85 (m, 3H), 6.62(br., 1H), 6.85 (m, 1H), 6.95 (m, 1H), 7.00-7.20 (m, 4H), 7.22-7.35 (m,1H).

[1250] MS (electrospray): M/Z (MH⁺) 405.1; C₂₀H₂₄N₂O₃S₂+H requires405.1.

[1251] Preparation 126

[1252] To a solution of 3-(3-thienyl)propanoic acid (200 mg, 1.2 mmol)in N,N-dimethylformamide (25 ml) was added 1-hydroxybenzotriazolemonohydrate (200 mg, 1.31 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (340 mg,1.77 mmol). After stirring at room temperature for 10 min the mixturewas treated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 400 mg, 1.3 mmol) and sodium hydrogen carbonate (220mg, 2.6 mmol). The reaction mixture was stirred at room temperature for72 h before concentrating in vacuo. Water (15 ml) was added and thereaction mixture was extracted with ethyl acetate (1×20 ml and 2×15 ml).The combined organic extracts were washed with water (15 ml) andsaturated brine (15 ml), dried (MgSO₄), and concentrated in vacuo togive a buff solid. The crude product was sonicated in methanol (5 ml) toafford the title compound as an off-white solid (330 mg, 63%, m.p.179.7° C.).

[1253] NMR (CDCl₃, selected data): 1.20 (s, 3H), 1.95 (m, 2H), 2.55 (m,2H), 2.90-3.10 (m, 5H), 3.50 (m, 1H), 3.60-3.80 (m, 3H), 6.60 (br., 1H),6.95-7.15 (m, 5H), 7.20-7.30 (m, 2H).

[1254] MS (electrospray): M/Z (MH⁺) 405.1; C₂₀H₂₄N₂O₃S₂+H requires405.1.

[1255] Preparation 127

[1256] To a solution of 1-benzofuran-2-carboxylic acid (201 mg, 1.24mmol) in N,N-dimethylformamide (25 ml) was added 1-hydroxybenzotriazolemonohydrate (200 mg, 1.31 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (340 mg,1.77 mmol). After stirring at room temperature for 10 min the mixturewas treated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 400 mg, 1.3 mmol) and sodium hydrogen carbonate (220mg, 2.6 mmol). The reaction mixture was stirred at room temperatureovernight before concentrating in vacuo. Water (15 ml) was added and thereaction mixture was extracted with ethyl acetate (2×20 ml). Thecombined organic extracts were treated with water (15 ml) upon which abuff solid precipitated. The biphasic mixture was filtered to afford 380mg of a buff solid. The biphasic filtrate was separated and the organiclayer was dried (MgSO₄), and concentrated in vacuo to afford a further80 mg of buff solid. The combined buff solid was warmed to 60° C. inmethanol and allowed to slowly cool to room temperature upon which thetitle compound was collected by filtration as an off-white solid (340mg, 63%).

[1257] NMR (DMSO, selected data): 1.20 (s, 3H), 2.02 (m, 2H), 2.95 (s,3H), 3.75-3.90 (m, 2H), 4.02 (m, 1H), 4.25 (m, 1H), 7.00-7.08 (m, 2H),7.15 (s, 1H), 7.2-7.35 (m, 2H), 7.45 (dd, 1H), 7.55 (s, 1H), 7.68 (d,1H), 7. 78 (d, 1H).

[1258] MS (electrospray): M/Z (MH⁺) 411.1; C₂₂H₂₂N₂O₄S+H requires 411.1.

[1259] Preparation 128

[1260] To a solution of 3-(5-fluoro-3-methyl-1H-indol-2-yl)propanoicacid (prepared according to the method described in EP 510398 A2, 200mg, 0.90 mmol) in N,N-dimethylformamide (20 ml) was added1-hydroxybenzotriazole monohydrate (154 mg, 1.00 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (262 mg,1.36 mmol). After stirring at room temperature for 10 min, the mixturewas treated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 308 mg, 0.90 mmol) and sodium hydrogen carbonate (150mg, 1.80 mmol). The reaction mixture was stirred at room temperatureovernight before concentrating in vacuo. Water (15 ml) was added and thereaction mixture was extracted with ethyl acetate (2×20 ml). Thecombined organic extracts were washed with water (15 ml), dried (MgSO₄),and concentrated in vacuo to afford 350 mg of a brown viscous oil whichwas not purified further.

[1261] NMR (CDCl₃, selected data): 1.15 (s, 3H), 1.95 (m, 2H), 2.20 (s,3H), 2.50 (m, 2H), 3.00 (s, 3H), 3.18 (m, 2H), 3.50 (m, 1H), 3.60-3.80(m, 3H), 6.60 (br. s, 1H), 6.82 (dd, 1H), 7.00-7.15 (m, 4H), 7.18 (m,1H), 7.25 (m, 1H).

[1262] MS (electrospray): M/Z (MH⁺) 470.2; C₂₅H₂₈FN₃O₃S+H requires470.2.

[1263] Preparation 129

[1264] To a solution of 3-(2-pyridinyl)propanoic acid (preparedaccording to the method described in WO 9730045 A1, 32 mg, 0.212 mmol)in N,N-dimethylformamide (2 ml) was added 1-hydroxybenzotriazolemonohydrate (32 mg, 0.209 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (41 mg,0.214 mmol). After stirring at room temperature for 10 min, the mixturewas treated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 64 mg, 0.212 mmol) and sodium hydrogen carbonate (36mg, 0.424 mmol). The reaction mixture was stirred at room temperaturefor 5 d. Water (5 ml) was added and the reaction mixture was extractedwith dichloromethane (3×5 ml). The combined organic extracts were dried(MgSO₄), and concentrated in vacuo to afford 70 mg of a brown oil. Thiswas purified by chromatography using a Biotage Flash 12™ cartridgepacked with silica gel (8 g) eluting with dichloromethane:ethanol:0.880ammonia (400:8:1) then 300:8:1) to afford the title compound as acolourless oil (17 mg, 20%).

[1265] NMR (CDCl₃, selected data): 1.18 (s, 3H), 1.95 (m, 2H), 2.75 (m,2H), 3.00 (s, 3H), 3.20 (dd, 2H), 3.60 (m, 1H), 3.70 (m, 2H), 3.80 (dd,1H), 7.00-7.18 (m, 4H), 7.20-7.30 (m, 2H), 7.45 (br. s, 1H), 7.58 (m,1H), 8.50 (d, 1H).

[1266] MS (electrospray): M/Z (M+H⁺) 400.2; C₂₁H₂₅N₃O₃S+H requires400.2. M/Z (MNa⁺) 422.2; C₂₁H₂₅N₃O₃S+Na requires 422.2.

[1267] IR ?_(max) (polyethylene card)/cm⁻¹ : 2360 (s), 2341 (m), 1624(m), 1437 (w), 1238 (w), 1154(w).

[1268] Preparation 130

[1269] To a solution of 3-(3-methyl-2-thienyl)propanoic acid (J. W.McFarland et al., J. Med. Chem., 1970, 13, 113, 200 mg, 1.17 mmol) inN,N-dimethylformamide (25 ml) was added 1-hydroxybenzotriazolemonohydrate (200 mg, 1.31 mmol) and1-(3-dimethylaminopropyl1)-3-ethylcarbodiimde hydrochloride (340 mg,1.77 mmol). After stirring at room temperature for 10 min. the mixturewas treated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 400 mg, 1.32 mmol) and sodium hydrogen carbonate (200mg, 2.38 mmol). The reaction mixture was stirred at room temperatureovernight and then concentrated in vacuo. Water (10 ml) was added andthe reaction mixture was extracted with ethyl acetate (2×15 ml). Thecombined organic extracts were washed with water (10 ml), dried (MgSO₄),and concentrated in vacuo to afford 620 mg of a brown oil. This waspurified by chromatography using a Biotage Flash 12™ cartridge packedwith silica gel (8 g) eluting with hexane:ethyl acetate (100:0 to 0:100over 30 min) and then with ethyl acetate:methanol (100:0 to 0:100 over 5min) to afford the title compound as a colourless oil (244 mg, 50%).

[1270] NMR (CDCl₃, selected data): 1.19 (s, 3H), 1.95 (m, 2H), 2.20 (s,3H), 2.48 (m, 2H), 3.00 (s, 3H), 3.15 (dd, 2H), 3.55 (m, 1H), 3.70-3.80(m, 1H), 6.65 (br. s 1H), 6.78 (d, 1H), 7.00-7.15 (m, 4H), 7.25 (m, 1H).

[1271] MS (electrospray): M/Z (MH⁺) 419.1; C₂₁H₂₆N₂O₃S₂+H requires419.1. M/Z (MNa⁺) 441.1; C₂₁H₂₅N₃O₃S+Na requires 441.1.

[1272] Preparation 131

[1273] To a solution of 3-(2-chlorophenyl)propanoic acid (200 mg, 1.08mmol) in N,N-dimethylformamide (20 ml) was added 1-hydroxybenzotriazolemonohydrate (187 mg, 1.22 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (318 mg,1.66 mmol). After stirring at room temperature for 10 min, the mixturewas treated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 400 mg, 1.32 mmol) and sodium hydrogen carbonate (200mg, 2.38 mmol). The reaction mixture was stirred at room temperature for3 d and then concentrated in vacuo. Water (15 ml) was added and thereaction mixture was extracted with ethyl acetate (2×20 ml). Thecombined organic extracts were washed with water (10 ml), dried (MgSO₄),and concentrated in vacuo to afford 510 mg of a light brown oil.Sonication for 5 min at room temperature in dichloromethane (5 ml)followed by filtration afforded the title compound as an off-white solid(124 mg, 27%).

[1274] NMR (CDCl₃, selected data): 1.18 (s, 3H), 1.95 (m, 2H), 2.60 (t,2H), 3.00 (s, 3H), 3.12 (dd, 2H), 3.55 (m, 1H), 3.70-3.80 (m, 3H), 6.55(br. s 1H), 7.00-7.20 (m, 4H), 7.25-7.40 (m, 4H).

[1275] MS (thermospray): M/Z (MH⁺) 433.1; C₂₂H₂₅ClN₂O₃S+H requires433.1.

[1276] Preparation 132

[1277] To a solution of (E)-3-(3-thienyl)-2-propenoic acid (200 mg, 1.08mmol) in N,N-dimethylformamide. (20 ml) was added 1-hydroxybenzotriazolemonohydrate (225 mg, 1.47 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (328 mg,1.71 mmol). After stirring at room temperature for 10 min, the mixturewas treated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 449 mg, 1.48 mmol) and sodium hydrogen carbonate (225mg, 2.68 mmol). The reaction mixture was stirred at room temperature for7 d and then concentrated in vacuo. Attempted partition between water(10 ml) and ethyl acetate (15 ml) produced a buff solid which wascollected by filtration. Sonication for 5 min at room temperature indichloromethane (5 ml) followed by filtration afforded the titlecompound as an off-white solid (430 mg, 72%).

[1278] NMR (DMSO, selected data) 1.18 (s, 3H), 1.95 (ddd, 2H), 2.95 (s,3H), 3.58 (d, 1H), 3.68 (dd, 1H), 3.82 (d, 1H), 3.95 (dd, 1H), 6.78 (d,1H), 6.98-7.05 (m, 2H), 7.10 (s, 1H), 7.22 (dd, 1H), 7.45 (d, 1H),7.52-7.60 (m, 2H), 7.83 (m, 1H).

[1279] MS (thermospray): M/Z (MH⁺) 403.1; C₂₀H₂₂N₂O₃S₂+H requires 403.1.

[1280] Preparation 133

[1281] To a solution of (E)-3-(2-thienyl) 2-propenoic acid (200 mg, 1.08mmol) in N,N-dimethylformamide (20 ml) was added 1-hydroxybenzotriazolemonohydrate (225 mg, 1.47 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (328 mg,1.71 mmol). After stirring at room temperature for 10 min, the mixturewas treated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 449 mg, 1.48 mmol) and sodium hydrogen carbonate (225mg, 2.68 mmol). The reaction mixture was stirred at room temperature for7 d and then concentrated in vacuo. Attempted partition between water(15 ml) and ethyl acetate (20 ml) produced a buff solid which wascollected by filtration. Sonication for 5 min at room temperature indichloromethane (5 ml) followed by filtration afforded the titlecompound as an off-white solid (337 mg, 77%).

[1282] NMR (DMSO, selected data): 1.18 (s, 3H), 1.95 (ddd, 2H), 2.95 (s,3H), 3.58 (d, 1H), 3.68 (dd, 1H), 3.80 (d, 1H), 3.95 (dd, 1H), 6.60 (d,1H), 6.95-7.05 (m, 2H), 7.10-7.15 (m, 2H), 7.22 (dd, 1H), 7.43 (d, 1H),7.58-7.65 (m, 2H).

[1283] MS (thermospray): M/Z (MH⁺) 403.0; C₂₀H₂₂N₂O₃S₂+H requires 403.1.

[1284] Preparation 134

[1285] To a solution of (E)-3-(3-methyl-2-thienyl)-2-propenoic acid (200mg, 1.00 mmol) in N,N-dimethylformamide (20 ml) was added1-hydroxybenzotriazole monohydrate (212 mg, 1.39 mmol) and1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (352 mg, 1.84mmol). After stirring at room temperature for 10 min, the mixture wastreated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 414 mg, 1.36 mmol) and sodium hydrogen carbonate (225mg, 2.68 mmol). The reaction mixture was stirred at room temperature for7 d and then concentrated in vacuo. Attempted partition between water(15 ml) and ethyl acetate (20 ml) produced a buff solid which wascollected by filtration. Sonication for 5 min at room temperature indichloromethane (5 ml) followed by filtration afforded the titlecompound as an off-white solid (280 mg, 67%).

[1286] NMR (DMSO, selected data): 1.18 (s, 3H), 1.95 (ddd, 2H), 2.28 (s,3H), 2.95 (s, 3H), 3.59 (d, 1H), 3.70 (dd, 1H), 3.80 (d, 1H), 3.97 (dd,1H), 6.47 (d, 1H), 6.95 (d, 1H), 6.97-7.03 (m, 2H), 7.10 (s, 2H), 7.22(dd, 1H), 7.43 (d, 1H), 7.58-7.65 (m, 2H).

[1287] MS (thermospray): M/Z (MH⁺) 417.1; C₂₁H₂₄N₂O₃S₂+H requires 417.1.

[1288] Preparation 135

[1289] To a solution of 3-nitroacetophenone (200 g, 1.12 mol) inIndustrial Methylated Spirits (1.2 l) was added hydrazine monohydrate(140 ml, 2.25 mol) and the reaction mixture was heated under reflux for2 h. Water (1.2 l) was added and the reaction mixture was cooled to roomtemperature. The resulting precipitate was collected by filtration toafford the title compound as a yellow crystalline solid (180 g, 82%).

[1290] NMR (CDCl₃, selected data): 2.15 (s, 3H), 5.52 (br. s, 2H), 7.48(dd, 1H), 7.99 (d, 1H), 8.12 (d, 1H), 8.46 (s, 1H).

[1291] MS (APCI): m/z (MH⁺) 180.5; C₈H₉N₃O₂+H requires 180.1.

[1292] Preparation 136

[1293] To a solution of 1-(3-nitrophenyl)-1-ethanone hydrazone(Preparation 135, 100 g, 0.56 mol) in dioxan (1 l) was added manganese(IV) oxide (200 g, 2.3 mol) and the reaction mixture was stirred at roomtemperature for 30 min. The suspension was filtered through Celite™washing with dioxan (ca. 200 ml).1-(3-Phenylpropyl)-1H-pyrrole-2,4-dione (Preparation 80, 110 g, 0.54mol) was added to the filtrate and the reaction mixture was stirred atroom temperature for 4 h before heating under reflux for 16 h. Thereaction mixture was cooled to room temperature and concentrated invacuo. The residue was triturated in methanol (500 ml) and theprecipitate was collected by filtration to afford the title compound asa white crystalline solid (121 g, 65%).

[1294] NMR (CDCl₃, selected data): 1.51 (m, 3H), 1.93 (m, 2H), 2.65 (t,2H), 2.77 (s, 2H), 3.50 (t, 2H), 7.15-7.19 (m, 3H), 7.24-7.30 (m, 2H),7.54 (dd, 1H), 7.65 (d, 1H), 8.15 (d, 1H), 8.19 (s, 1H).

[1295] MS (APCI): m/z (MH⁺) 365.5; C₂₁H₂₀N₂O₄+H requires 365.2.

[1296] Preparation 137

[1297] To a solution of 2′-nitroacetophenone (8.26 g, 50.00 mmol) inethanol (50 ml) was added hydrazine monohydrate (4.85 ml, 100 mmol) andthe reaction mixture was heated at 70° C. for 5 h. The reaction mixturewas cooled to room temperature and water (100 ml) was added. After 5 d,the reaction mixture was concentrated in vacuo to ca. 100 ml and diethylether (100 ml) was added. The layers were separated and the aqueouslayer was extracted with diethyl ether (100 ml). The combined extractswere dried (Na₂SO₄) and concentrated in vacuo to afford ca. 8.0 g of acrude yellow oil. This was purified by chromatography in two batchesusing a Biotage Flash 40M™ cartridge packed with silica gel (90 g)eluting with dichloromethane:diethyl ether (19:1) to afford the titlecompound as viscous yellow oil (4.20 g, 45%).

[1298] NMR (CDCl₃, selected data): 2.05 (s, 3H), 5.40 (br. s, 2H),7.42-7.50 (m, 2H), 7.60 (dd, 1H), 7.90 (d, 1H).

[1299] Preparation 138

[1300] To a solution of 1-(2-nitrophenyl)-1-ethanone hydrazone(Preparation 137, 4.00 g, 22.3 mmol) in dioxan (50 ml) was addedmanganese (IV) oxide (4.27 g, 49.2 mmol) followed by a saturatedethanolic solution of potassium hydroxide (2.0 ml), and the reactionmixture was stirred at room temperature for 4 h. The suspension wasfiltered through Celite™ washing with dioxan (ca. 150 ml) to give a deepred solution. 1-Hexyl-1H-pyrrole-2,4-dione (Preparation 56, 4.05 g, 22.4mmol) was added to the solution and the reaction mixture was stirred atroom temperature overnight before heating under reflux for 24 h. Thereaction mixture was cooled to room temperature, filtered throughCelite™ and concentrated in vacuo a crude dark brown oil. This waspurified by chromatography in two batches using a Biotage Flash 40M™cartridge packed with silica gel (90 g) eluting withdichloromethane:hexane (2:1) to afford an 8:1 exo:endo mixture ofdiastereomers of the title compound as a pale brown oil (880 mg, 12%).

[1301] NMR (CDCl₃, selected data for the exo isomer): 0.90 (m, 3H),1.25-1.40 (m, 6H), 1.55-1.60 (m, 5H), 2.62 (s, 2H), 3.42 (m, 2H), 7.45(m, 1H), 7.60-7.65 (m, 2H), 7.95 (d, 1H).

[1302] NMR (CDCl₃, selected data for the endo isomer): 0.82 (m, 3H),1.20-1.30 (m, 6H), 1.45 (m, 2H), 2.22 (s, 3H), 3.30-3.48 (m, 4H), 7.20(d, 1H), 7.52 (dd, 1H), 7.62 (dd, 1H), 8.18 (d, 1H).

[1303] MS (electrospray): m/z (MH⁺) 331.2; C₁₈H₂₂N₂O₄+H requires 331.2.m/z (MNa⁺) 353.1; C₁₈H₂₂N₂O₄+Na requires 353.1.

[1304] Preparation 139

[1305] To a solution of3-hexyl-6-methyl-6-(2-nitrophenyl)azabicyclo[3.1.0]hexane-2,4-dione(Preparation 138, 880 mg, 2.66 mmol) in tetrahydrofuran (10 ml) wasadded 5% palladium on charcoal (Johnsson Matthey type 87, 50 mg) and thereaction mixture was placed under an atmosphere of hydrogen (60 psi) atroom temperature for 4 h. The catalyst was removed by filtration throughCelite™ and the filtrate was concentrated in vacuo . The residue wasflushed through a small plug of silica gel (<1 g) eluting withdichloromethane to afford only the exo isomer of the title compound as apale yellow oil (310 mg, 39%).

[1306] NMR (CDCl₃, selected data): 0.90 (m, 3H), 1.15-1.40 (m, 6H), 1.45(m, 2H), 1.60 (s, 3H), 2.75 (m, 2H), 3.45 (m, 2H), 3.90 (br. s 2H),6.65-6.80 (m, 2H), 7.08-7.18 (m, 2H).

[1307] MS (thermospray): m/z (MH⁺) 301.1; C₁₈H₂₂N₂O₂+H requires 301.2.

[1308] Preparation 140

[1309] To a solution of6-(2-aminophenyl)-3-hexyl-6-methylazabicyclo[3.1.0]hexane-2,4-dione(Preparation 139, 310 mg, 1.03 mmol) in tetrahydrofuran (10 ml) undernitrogen at 0° C. was added dropwise a 1.0M solution of lithiumaluminium hydride in tetrahydrofuran (2.5 ml, 2.5 mmol), and thereaction mixture was allowed to stir at room temperature for 4 h. Therapidly stirred reaction mixture was treated sequentially with water(2.5 ml), sodium carbonate (2.5 g) and ethyl acetate (25 ml). Thereaction mixture was stirred for 1 h, filtered and concentrated invacuo. This was purified by chromatography using a Biotage Flash 12™cartridge packed with silica gel (8 g) eluting with ethylacetate:hexane:0.880 ammonia (25:75:1) to afford the title compound as apale yellow oil (123 mg, 44%).

[1310] NMR (CDCl₃, selected data): 0.90 (m, 3H), 1.15-1.40 (m, 6H), 1.45(m, 2H), 1.60 (s, 3H), 2.75 (m, 2H), 3.45 (m, 2H), 3.90 (br. s 2H),6.65-6.80 (m, 2H), 7.08-7.18 (m, 2H).

[1311] MS (electrospray): m/z (MH⁺) 267.2; C₁₈H₂₂N₂+H requires 267.2.

[1312] Preparation 141

[1313] A solution of 1-hydroxybenzotriazole monohydrate (224 mg, 1.46mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(306 mg, 1.60 mmol) in N,N-dimethylformamide (10 ml) was added to(E)-3-(2-pyridinyl)-2-propenoic acid (197 ng, 1.32 mmol). After stirringat room temperature for 15 min, the mixture was added to thehydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 404 mg, 1.32 mmol) and sodium hydrogen carbonate (220mg, 2.64 mmol). The reaction mixture was stirred at room temperature forovernight and then water (20 ml) and dichloromethane (10 ml) were added.The biphasic mixture was separated by filtering through a WhatmanMicrofiltration Device Filter Tube, and the resulting organic extractwas concentrated using a stream of nitrogen to afford 377 mg of a crudedark brown oil. This was purified by chromatography using a BiotageFlash 40S™ cartridge packed with silica gel (40 g) eluting withdichloromethane:ethanol:0.880 ammonia (100:2:1) to afford the titlecompound as a white solid (172 mg, 33%).

[1314] NMR (CDCl₃, selected data) 1.25 (s, 3H), 2.02 (m, 2H), 3.00 (s,3H), 3.80-3.95 (m, 3H), 4.05 (dd, 1H), 7.05-7.18 (m, 2H), 7.20-7.30 (m,3H), 7.35 (d, 1H), 7.41 (d, 1H), 7.72 (dd, 1H), 7.79 (d, 1H), 8.62 (d,1H).

[1315] MS (electrospray): M/Z (MH⁺) 398; C₂₁H₂₃N₃O₃S+H requires 398.

[1316] Preparation 142

[1317] A solution of 1-hydroxybenzotriazole monohydrate (112 mg, 0.73mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(153 mg, 0.80 mmol) in N,N-dimethylformamide (5 ml) was added to(E)-3-(2-quinolinyl)-2-propenoic acid (M. Hamana, K. Funakoshi and Y.Kuchino, Chem. Pharm. Bull., 1974, 22, 1806; 131 mg, 0.66 mmol). Afterstirring at room temperature for 15 min, the mixture was added to thehydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 202 mg, 0.66 mmol) and sodium hydrogen carbonate (110mg, 1.32 mmol). The reaction mixture was stirred at room temperature forovernight and then water (10 ml) and dichloromethane (5 ml) were added.The biphasic mixture was separated by filtering through a WhatmanMicrofiltration Device Filter Tube, and the resulting organic extractwas concentrated using a stream of nitrogen to afford 400 mg of a crudedark red oil. This was purified by chromatography using a Biotage Flash40S™ cartridge packed with silica gel (40 g) eluting withdichloromethane:ethanol:0.880 ammonia (100:2:1) to afford the titlecompound as a cream solid (206 mg, 70%).

[1318] NMR (CDCl₃, selected data): 1.32 (s, 3H), 2.05 (m, 2H), 3.02 (s,3H), 3.85-3.95 (m, 2H), 4.00 (d, 1H), 4.15 (dd, 1H), 6.88 (br. s, 1H),7.15 (dd, 1H), 7.20-7.35 (m, 2H), 7.48 (d, 1H), 7.52-7.60 (m, 2H), 7.75(dd, 1H), 7.82 (d, 1H), 7.95 (d, 1H), 8.12 (d, 1H), 8.19 (d, 1H).

[1319] MS (electrospray): M/Z (MH⁺) 448; C₂₅H₂₅N₃O₃S+H requires 448.

[1320] Preparation 143

[1321] A solution of 1-hydroxybenzotriazole monohydrate (112 mg, 0.73mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(153 mg, 0.80 mmol) in N,N-dimethylformamide (5 ml) was added to3-(1,3-benzothiazol-2-yl)propanoic acid (P. Baudet and C. Otten, Helv.Chim. Acta, 1970, 53, 1683; 137 mg, 0.66 mmol). After stirring at roomtemperature for 15 min, the mixture was added to the hydrochloride saltof N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 202 mg, 0.66 mmol) and sodium hydrogen carbonate (110mg, 1.32 mmol). The reaction mixture was stirred at room temperature forovernight and then water (10 ml) and dichloromethane (5 ml) were added.The biphasic mixture was separated by filtering through a WhatmanMicrofiltration Device Filter Tube, and the resulting organic extractwas concentrated using a stream of nitrogen to afford 326 mg of a crudedark green solid. This was purified by chromatography using a BiotageFlash 40S™ cartridge packed with silica gel (40 g) eluting withdichloromethane:ethanol:0.880 ammonia (100:2:1) to afford the titlecompound as an off-white solid (228 mg, 76%).

[1322] NMR (CDCl₃, selected data): 1.30 (s, 3H), 2.02 (m, 2H), 3.00 (s,3H), 3.78-3.90 (m, 3H), 4.00 (dd, 1H), 6.47 (br. s, 1H), 6.63 (d, 1H),7.03-7.15 (m, 3H), 7.29 (dd, 1H), 7.46 (dd, 1H), 7.56 (dd, 1H),7.67-7.73 (m, 2H), 8.06 (d, 1H).

[1323] MS (electrospray): M/Z (MH⁺) 456; C₂₃H₂₅N₃O₃S₂+H requires 456.

[1324] Preparation 144

[1325] A solution of 1-hydroxybenzotriazole monohydrate (112 mg, 0.73mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(153 mg, 0.80 mmol) in N,N-dimethylformamide (5 ml) was added to(E)-3-(6-methyl-2-pyridinyl)-2-propenoic acid (F. Freeman, L. Y. Chang,J. C. Kappos and L. Sumarta, J. Org. Chem., 1987, 52, 1460; 108 mg, 0.66mmol). After stirring at room temperature for 15 min, the mixture wasadded to the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 202 mg, 0.66 mmol) and sodium hydrogen carbonate (110mg, 1.32 mmol). The reaction mixture was stirred at room temperature forovernight and then water (10 ml) and dichloromethane (5 ml) were added.The biphasic mixture was separated by filtering through a WhatmanMicrofiltration Device Filter Tube, and the resulting organic extractwas concentrated using a stream of nitrogen to afford 290 mg of a crudecream solid. This was purified by chromatography using a Biotage Flash40S™ cartridge packed with silica gel (40 g) eluting withdichloromethane ethanol:0.880 ammonia (100:2:1) to afford the titlecompound as a white solid (191 mg, 70%).

[1326] NMR (CDCl₃, selected data) 1.27 (s, 3H), 2.02 (m, 2H), 2.60 (s,3H), 3.01 (s, 3H), 3.82-3.98 (m, 3H), 4.08 (dd, 1H), 6.87 (br. s, 1H),7.07-7.15 (m, 2H), 7.19-7.37 (m, 5H), 7.59 (dd, 1H), 7.73 (d, 1H).

[1327] MS (electrospray): M/Z (MH⁺) 412; C₂₂H₂₅N₃O₃S+H requires 412.

[1328] Preparation 145

[1329] A solution of 1-hydroxybenzotriazole monohydrate (112 mg, 0.73mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(153 mg, 0.80 mmol) in N,N-diethylformamide (5 ml) was added to(E)-3-(2-(trifluoromethyl)phenyl)-2-propenoic acid (143 mg, 0.66 mmol).After stirring at room temperature for 15 min, the mixture was added tothe hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 202 mg, 0.66 mmol) and sodium hydrogen carbonate (110mg, 1.32 mmol). The reaction mixture was stirred at room temperature forovernight and then water (10 ml) and dichloromethane (5 ml) were added.The biphasic mixture was separated by filtering through a WhatmanMicrofiltration Device Filter Tube, and the resulting organic extractwas concentrated using a stream of nitrogen to afford 364 mg of a crudebrown oil. This was purified by chromatography using a Biotage Flash40S™ cartridge packed with silica gel (40 g) eluting withdichloromethane:ethanol:0.880 ammonia (100:2:1) to afford the titlecompound as a yellow oil (240 mg, 78%).

[1330] NMR (CDCl₃, selected data) 1.30 (s, 3H), 2.02 (m, 2H), 3.00 (s,3H), 3.78-3.90 (m, 3H), 4.00 (dd, 1H), 6.47 (br. s, 1H), 6.63 (d, 1H),7.03-7.15 (m, 3H), 7.29 (dd, 1H), 7.46 (dd, 1H), 7.56 (dd, 1H),7.67-7.73 (m, 2H), 8.06 (d, 1H).

[1331] MS (electrospray): M/Z (MH⁺) 465; C₂₃H₂₃F₃N₂O₃S+H requires 465.

[1332] Preparation 146

[1333] To a solution of 4-phenylbutanoic acid (219 mg, 1.33 mmol) inN,N-dimethylformamide (20 ml) was added 1-hydroxybenzotriazolemonohydrate (225 mg, 1.48 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (382 mg,1.98 mmol). After stirring at room temperature for 15 min the mixturewas treated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 449 mg, 1.48 mmol) and sodium hydrogen carbonate (225mg, 2.7 mmol). The reaction mixture was stirred at room temperature forovernight before concentrating in vacuo. Water (15 ml) was added and thereaction mixture was extracted with ethyl acetate (20, 15 ml). Thecombined organic extracts were washed with water (15 ml), dried (MgSO₄),filtered and concentrated in vacuo to give a colourless oil (540 mg).This was purified by chromatography using a Biotage Flash 12™ cartridgepacked with silica gel (8 g) eluting with hexane:ethyl acetate (100:0 to0:100 over 30 min) and then with ethyl acetate:methanol (100:0 to 0:100over 5 min) to afford the title compound as a colourless glass (360 mg,59%).

[1334] NMR (CDCl₃, selected data): 1.25 (s, 3H), 1.90-2.10 (m, 4H), 2.25(t, 2H), 2.70 (t, 2H), 3.00 (s, 3H), 3.50 (d, 1H), 3.65-3.80 (m, 3H),6.70 (br. s, 1H), 7.00-7.40 (m, 9H).

[1335] MS (electrospray): M/Z (MH⁺) 413; C₂₃H₂₈N₂O₃S+H requires 413.

[1336] Preparation 147

[1337] To a solution of 3-(2-methoxyphenyl)propanoic acid (240 mg, 1.33mmol) in N,N-dimethylformamide (20 ml) was added 1-hydroxybenzotriazolemonohydrate (225 mg, 1.48 mmol) and1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (382 mg, 1.98mmol). After stirring at room temperature for 15 min the mixture wastreated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 449 mg, 1.48 mmol) and sodium hydrogen carbonate (225mg, 2.7 mmol). The reaction mixture was stirred at room temperature forovernight before concentrating in vacuo. Water (15 ml) was added and thereaction mixture was extracted with ethyl acetate (20, 15 ml). Thecombined organic extracts were washed with water (15 ml), dried (MgSO₄),filtered and concentrated in vacuo to give a dark buff solid (470 mg).The crude product was sonicated in dichloromethane (5 ml) and collectedby filtration to afford the title compound as an off-white solid (220mg, 39%).

[1338] NMR (CDCl₃, selected data): 1.18 (s, 3H), 1.93 (m, 2H), 2.58 (dd,2H), 2.95-3.02 (m, 5H), 3.52 (d, 1H), 3.65-3.77 (m, 3H), 3.85 (s, 3H),6.58 (b)r. s, 1H), 6.80-6.92 (m, 2H), 7.00-7.30 (m, 6H).

[1339] MS (electrospray): M/Z (MH⁺) 429; C₂₃H₂₈N₂O₄S+H requires 429.

[1340] Preparation 148

[1341] To a solution of 1-benzothiophene-2-carboxylic acid (236 mg, 1.33mmol) in N,N-dimethylformamide (20 ml) was added 1-hydroxybenzotriazolemonohydrate (225 mg, 1.48 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride (382 mg, 1.98mmol). After stirring at room temperature for 15 min the mixture wastreated with the hydrochloride salt ofN-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide(Preparation 53, 449 mg, 1.48 mmol) and sodium hydrogen carbonate (225mg, 2.7 mmol). The reaction mixture was stirred at room temperature forovernight before concentrating in vacuo. Water (15 ml) was added and thereaction mixture was extracted with ethyl acetate (20, 15 ml). Thecombined organic extracts were washed with water (15 ml), dried (MgSO₄),filtered and concentrated in vacuo to give a buff solid (545 mg). Thecrude product was sonicated in dichloromethane (5 ml) and collected byfiltration to afford the title compound as an off-white solid (410 mg,72%).

[1342] NMR (DMSO, selected data): 1.20 (s, 3H), 2.03 (m, 2H), 3.00 (m,3H), 3.80-4.00 (m, 3H), 4.25 (m, 1H), 7.00-7.08 (m, 2H), 7.12 (s, 1H),7.24 (dd, 1H), 7.40-7.50 (m, 2H), 7.93-8.03 (m, 3H).

[1343] MS (electrospray): M/Z (MH⁺) 427; C₂₂H₂₂N₂O₃S₂+H requires 427.

1. A substance which is a compound of formula I,

wherein the “Ar” ring represents an optionally benzo-fused phenyl or 5-or 6-membered heteroaryl ring; R¹ when taken alone is H, halogen, NO₂,NH₂, NY²WY¹, Het¹, AD, CO₂R⁷, C(O)R⁸, C(═NOH)R⁸, or OE, Y² is H, C₁₋₆alkyl, C₃₋₆ alkenyl (each of which alkyl and alkenyl is optionallysubstituted by aryl, aryloxy or Het¹), W is SO₂, CO, C(O)O, P(Y¹)═O,P(Y¹)═S, Y¹ is C₁₋₁₀ alkyl (optionally substituted by one or moresubstituents independently selected from halogen, OH, C₁₋₄ alkoxy, C₁₋₆alkanoyloxy, CONH₂, C₁₋₆ alkoxycarbonyl, NH₂, aryl, mono- or di(C₁₋₄alkyl)amino, C₃₋₈ cycloalkyl, phthalimidyl, Het¹), Het¹, aryl(optionally substituted by one or more substituents independentlyselected from C₁₋₄ alkyl, C₁₋₄ haloalkyl and halogen), NH₂, N(C₁₋₆alkyl)₂ or NH(C₁₋₆ alkyl), Het¹ is a heterocyclic group containing up to4 heteroatoms selected from N, O and S, which may comprise up to 3 rings(preferably a heteroaryl group, optionally benzo- or pyrido-fusedheteroaryl), optionally substituted by one or more substituentsindependently selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkyl,C₁₋₆ haloalkoxy, C₃₋₆ haloalkyl, C₃₋₆ halocycloalkyl, ═O, OH, halogen,NO₂, SiR^(19a)R^(19b)R^(19c), CON^(20a)R^(20b), NR^(20a)R^(20b),SR^(21a), NR^(21b)SO₂R^(22a), NR^(21c)C(O)OR^(22b), NR^(21d)COR^(22d),and C₁₋₆ alkoxycarbonyl, and if a S atom is present in a ring, it can bepresent as part of a —S—, S(O)— or —S(O₂)— group, and carbon atoms inthe ring can be present as a part of a carbonyl moiety; R^(19a),R^(19b), R^(19c) each independently represent C₁₋₆ alkyl or aryl,R^(20a) and R^(20b) each independently represent H, C₁₋₆ alkyl, aryl,(C₁₋₄ alkyl)phenyl, each of which alkyl, aryl and alkylphenyl areoptionally substituted by one or more C₁₋₄ alkyl, C₁₋₄ alkoxy, OH, NO₂,NH₂ and/or halogen, or R^(20a) and R^(20b) can be taken together withthe N atom to which they are attached, to form a 4- to 6-membered ringoptionally substituted by one or more substitutuents independentlyselected from one or more C₁₋₄ alkyl, C₁₋₄ alkoxy, OH, ═O, NO₂, NH₂and/or halogen, R^(21a, b, c and d) each independently represent H, C₁₋₄alkyl, aryl or C₁₋₆ alkylphenyl, each of which alkyl, aryl, andalkylphenyl are optionally substituted by one or more C₁₋₄ alkyl, C₁₋₄alkoxy, OH, NO₂, halogen, NH₂, R^(22a, b and c) each independentlyrepresent C₁₋₆ alkyl, aryl or C₁₋₄ alkylphenyl, each of which alkyl,aryl, and alkylphenyl are optionally substituted by one or more C₁₋₄alkyl, C₁₋₄ alkoxy, OH, NO₂, halogen, NH₂, A is C₁₋₄ alkylene, C₂₋₄alkenylene or C₂₋₄ alkynylene, each of which is optionally substitutedby one or more C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen and/or OH, D is H, OH,CN, NR²⁵R²⁶, CONR²⁵R²⁶, NHR²⁷, CO₂R²⁸, COR²⁹, C(═NH)R²⁹, or AD is CN,NR²⁵R²⁶, CONR²⁵R²⁶, where R²⁵ and R²⁶ are either each independently H,C₁₋₃ alkyl, C₃₋₈ cycloalkyl, aryl, C₁₋₄ alkylphenyl (each of which C₁₋₃alkyl, C₃₋₈ cycloalkyl, aryl and C₁₋₄ alkylphenyl are optionallysubstituted by one or more NO₂, halogen, C₁₋₄ alkyl and/or C₁₋₄ alkoxy,(each of which latter C₁₋₄ alkyl and C₁₋₄ alkoxy is optionallysubstituted by one or more halogen)), or R²⁵ and R²⁶ are taken togetherwith the N atom to which they are attached and can form a 4- to7-membered heterocyclic ring optionally incorporating one or morefurther hetero atoms selected from N, O and S, and which ring isoptionally substituted by one or more C₁₋₄ alkyl, OH, ═O, NO₂, NH₂and/or halogen, R²⁷ is COR³⁰, CO₂R^(31a), SO₂R^(31b), R²⁸ and R²⁹ areeach independently H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, aryl orC₁₋₄alkylphenyl, each of which C₁₋₆ alkyl, C₃₋₈ cycloalkyl, aryl andC₁₋₄ alkylphenyl are optionally substituted by one or more NO₂, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy (each of which latter C₁₋₄ alkyl and C₁₋₄ alkoxyare optionally substituted by one or more halogen), R³⁰ is H, C₁₋₄alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, C₃₋₈ cycloalkyloxy, aryl, aryloxy,C₁₋₄ alkylphenyl, phenyl(C₁₋₄)alkoxy, (each of which C₁₋₄ alkyl, C₃₋₈cycloalkyl, C₁₋₄ alkoxy, C₃₋₈ cycloalkyloxy, aryl, aryloxy, C₁₋₄alkylphenyl and phenyl(C₁₋₄)alkoxy are optionally substituted by one ormore NO₂, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy (which latter alkyl andalkoxy are optionally substituted by one or more halogen)), R^(31a) andR^(31b) are each independently C₁₋₄ alkyl, C₃₋₈ cycloalkyl, aryl or C₁₋₄alkylphenyl, each of which is optionally substituted by one or more NO₂,halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy, each of which latter alkyl andalkoxy is optionally substituted by one more halogen E is H, CONR³²R³³,CSNR³²R³³, COR³⁴, CO₂R³⁴, COCH(R^(34a))NH₂, R³⁵, CH₂CO₂R^(35a),CHR^(35b)CO₂R^(35a), CH₂OCO₂R^(35c), CHR^(35d)OCO₂R^(35c),COCR³⁶═CR³⁷NH₂, COCHR³⁶CHR³⁷NH₂, or PO(OR³⁸)₂, R³² and R³³ are eachindependently H, C₃₋₁₀ alkylalkenyl, C₃₋₇ cycloalkyl (optionallysubstituted by C₁₋₄ alkyl), phenyl (optionally substituted by (X)_(n)),C₁₋₁₀ alkyl (optionally substituted by C₄₋₇ cycloalkyl (optionallysubstituted by C₁₋₄ alkyl) or phenyl optionally substituted by (X)_(n)),or R³² and R³³ can be taken together with the N atom to which they areattached and can form a 5- to 8-membered heterocycle optionallycomprising firther hetero atoms selected from N, O and S, whichheterocycle is optionally substituted by C₁₋₄ alkyl, optionallysubstituted by one or more halogen, R³⁴ is H, C₄₋₇ cycloalkyl(optionally substituted by one or more C₁₋₄ alkyl), phenyl (optionallysubstituted by (X)_(n), C₁₋₄ alkanoyloxy, NR³²R³³, CONR³²R³³ and/or OH),or C₁₋₆ alkyl (optionally substituted by one or more halogen, C₄₋₇cycloalkyl (optionally substituted by one or more C₁₋₄ alkyl), or phenyl(optionally substituted by (X)_(n), C₁₋₄ alkanoyloxy, NR³²R³³, CONR³²R³³and/or OH)), R^(34a) is H, C₁₋₆ alkyl (optionally substituted by one ormore halogen, C₄₋₇ cycloalkyl (optionally substituted by one or moreC₁₋₄ alkyl), or phenyl (optionally substituted by (X)_(n), C₁₋₄alkanoyloxy, NR³²R³³, CONR³²R³³ and/or OH)), C₄₋₇ cycloalkyl (optionallysubstituted by one or more C₁₋₄ alkyl), phenyl (optionally substitutedby (X)_(n), C₁₋₄ alkanoyloxy, NR³²R³³, CONR³²R³³ and/or OH) or anaturally occuring amino acid substituent, R³⁵ is C₄₋₇ cycloalkyloptionally substituted by one or more C₁₋₄ alkyl, phenyl (optionallysubstituted by one or more (X)_(n), C₁₋₄ alkanoyl, NHR³², CON(R³²)₂,and/or OH), C₁₋₆ alkyl (optionally substituted by C₄₋₇ cycloalkyloptionally substituted by one or more C₁₋₄ alkyl, or phenyl (optionallysubstituted by one or more (X)_(n), C₁₋₄ alkanoyl, NHR³², CON(R³²)₂,and/or OH)), C₁₋₄ alkoxy(C₁₋₄ alkyl), phenyl(C₁₋₄)alkyloxy(C₁₋₄)alkyl,tetrahydropyranyl, tetrahydrofuranyl, cinnamyl or trimethylsilyl,R^(35a, b, c and d) are each independently H, C₄₋₇ cycloalkyl optionallysubstituted by one or more C₁₋₄ alkyl, phenyl optionally substituted byone or more (X)_(n), or C₁₋₆ alkyl (optionally substituted by C₄₋₇cycloalkyl optionally substituted by one or more C₁₋₄ alkyl, or phenyloptionally substituted by one or more (X)_(n)), R³⁶ and R³⁷ eachindependently represent H, C₃₋₆ alkylalkenyl, C₄₋₇ cycloalkyl, phenyloptionally substituted by one or more (X)_(n), or C₁₋₆ alkyl (optionallysubstituted by C₄₋₇ cycloalkyl optionally substituted by one or moreC₁₋₄ alkyl, or phenyl optionally substituted by one or more (X)_(n)),R³⁸ is C₄₋₇ cycloalkyl optionally substituted by one or more C₁₋₄ alkyl,phenyl optionally substituted by one or more (X)_(n), or C₁₋₆ alkyl(optionally substituted by C₄₋₇ cycloalkyl optionally substituted by oneor more C₁₋₄ alkyl, or phenyl optionally substituted by one or more(X)_(n)), R² when taken alone is H or halogen; or R¹ and R², whenattached to adjacent carbon atoms, can be taken together with the carbonatoms to which they are attached, and may represent Het^(1a); Het^(1a)is a heterocyclic group containing up to 4 heteroatoms selected from N,O and S, which may comprise up to 3 rings (and is preferably anoptionally benzo-fused 5- to 7-membered heterocyclic ring) and whichgroup is optionally substituted by one or more substituentsindependently selected from OH, ═O, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy and C₁₋₄ haloalkoxy, which C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy and C₁₋₄ haloalkoxy groups can be optionally substituted by oneor more C₃₋₆ cycloalkyl, aryl(C₁₋₆)alkyl, which aryl group is optionallysubstituted by one or more halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy and C₁₋₄ haloalkoxy, which latter C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy and C₁₋₄ haloalkoxy groups can be optionally substituted byone or more NR²³R²⁴, NR²³S(O)_(n)R²⁴, NR²³C(O)_(m)R²⁴, and if a S atomis present in a ring, it can be present as part of a —S—, S(O)— or—S(O₂)— group, which R²³ and R²⁴ when taken alone independentlyrepresent H, C₁₋₄ alkyl, or C₁₋₄ haloalkyl, or R²³ and R²⁴ can be takentogether with the N atom to which they are attached, to form a 4- to6-membered heterocyclic ring optionally comprising one or more furtherheteroatoms selected from, N, O, or S, and which heterocyclic ring isoptionally substituted by one or more halogen, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy and/or C₁₋₄ haloalkoxy groups, R³ is H, CN,halogen, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₂₋₆ alkanoyl, C₂₋₆alkanoyloxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyloxy, C₄₋₉ cycloalkanoyl,aryl, aryloxy, heteroaryl, saturated heterocycle, NR¹²R¹³, CONR¹²R¹³,NY²WY¹, C₁₋₆ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, (each of which alkyl,alkenyl and alkynyl groups is optionally substituted by one or more CN,halogen, OH, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₂₋₆ alkyloxycarbonyloxy,C₁₋₆ alkanoyl, C₁₋₆ alkanoyloxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyloxy,C₄₋₉ cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle,NR¹²R¹³, CONR¹²R¹³ and/or NY²WY¹), R⁴ is C₁₋₁₀ alkyl, C₃₋₁₀ alkenyl orC₃₋₁₀ alkynyl each of which groups is linked to the N atom via a sp³carbon, and which is optionally substituted by one or more OH, CN,halogen, C₁₋₆ alkoxy (optionally substituted by aryl), aryloxy(optionally substituted by one or more halogen, C₁₋₆ alkyl(optionallysubstituted by one or more CN and/or halogen), C₁₋₄ alkoxy, C₁₋₄haloalkoxy, OH, ═O and/or NY²WY¹), C₁₋₆ alkoxycarbonyl, C₂₋₆ alkanoyl,C₂₋₆ alkanoyloxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyloxy, C₄₋₉cycloalkanoyl, aryl (optionally substituted by one or more halogen, C₁₋₆alkyl(optionally substituted by one or more CN and/or halogen), C₁₋₄alkoxy, C₁₋₄ haloalkoxy, OH, ═O and/or NY²WY¹), C₁₋₄ alkoxy, C₁₋₄haloalkoxy, OH, C₁₋₄ haloalkoxy, and/or NY²WY¹), heterocycle (optionallybenzo-fused and optionally substituted by one or more halogen, C₁₋₆alkyl(optionally substituted by one or more CN and/or halogen), C₁₋₄alkoxy, OH, ═O, C₁₋₄ haloalkoxy, and/or NY²WY¹), heterocyclyloxy(optionally substituted by one or more halogen, C₁₋₆ alkyl(optionallysubstituted by one or more CN and/or halogen), C₁₋₄ alkoxy, OH, ═O, C₁₋₄haloalkoxy, and/or NY²WY¹), adamantyl or ZBNR¹⁴R¹⁵, Z is a direct bond,CO or S(O)_(n) group, B is (CH₂)_(p), R¹² and R¹³ each independentlyrepresent H or C₁₋₄ alkyl, or R¹² and R¹³ can be taken together with theN atom to which they are attached to form a 4- to 7-membered heterocycleoptionally comprising a further hetero moiety selected from NR¹⁶, Oand/or S, and which is optionally substituted by one or more C₁₋₄ alkyl,R¹⁴ and R¹⁵ each independently represent H, C₁₋₁₀ alkyl, C₃₋₁₀ alkenyl,C₃₋₁₀ alkynyl, C₃₋₈ cycloalkyl, aryl or heteroaryl, or R¹⁴ and R¹⁵ canbe taken together with the N atom to which they are attached to form a4- to 7-membered heterocycle optionally comprising a further heteromoiety selected from NR¹⁶, O and/or S, and which is optionallysubstituted by one or more C₁₋₄ alkyl, R¹⁶ is H, C₁₋₆ alkyl, C₃₋₈cycloalkyl, (C₁₋₆ alkylene)(C₃₋₈ cycloalkyl) or (C₁₋₆ alkylene)aryl, R⁵and R⁸ when taken separately are each independently H, C₁₋₆ alkyl, R⁵and R⁸ can be taken together with the carbon atoms to which they arejoined to form a C₃₋₈ cycloalkyl ring, R⁶, R⁷, R⁹ and R¹⁰ when takenseparately are H, R⁵ and R⁶ or R⁷ can be taken together with the carbonatoms to which they are joined to form a C₃₋₈ cycloalkyl ring, X ishalogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl or C₁₋₄ haloalkoxy, mis 1 or 2; n is 0, 1 or 2; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; q is0 or 1; “Naturally occuring amino acid substituent” means theα-substituent that occurs in any one of the following natural aminoacids, glycine, alanine, valine, leucine, isoleucine, phenylalanine,tryptophan, tyrosine, histidine, serine, threonine, methionine,cysteine, aspartic acid, glutamic acid, asparagine, glutamine, lysine,arginine or proline; “Heteroaryl” represents an aromatic ring containingup to four heteroatoms independently selected from N, O and S, and if aS atom is present in the ring, it can be present as part of a —S—, S(O)—or —S(O)₂— group, and which may be joined to the remainder of thecompound via any available atom(s); “Heterocycle” is a group containing1, 2 or 3 rings, and which contains up to 4 ring heteroatoms selectedfrom N, O and S and up to 18 ring carbon atoms; “Aryl”, including in thedefinitions of “aryloxy”, etc., means a group comprising a phenyl ringand which may incorporate a further carbocyclic ring fused to saidphenyl ring and which may be joined to the remainder of the compound viaany available atom(s) (examples of such groups include naphthyl,indanyl, etc.); “Alkyl”, “alkenyl” and “alkynyl” groups can be linear orbranched if the number of carbon atoms allows; “Cycloalkyl” groups canbe polycyclic if the number of carbon atoms allows; or apharmaceutically or veterinarily acceptable derivative or prodrugthereof.
 2. A substance according to claim 1 wherein the “Ar” ringrepresents phenyl or pyridyl.
 3. A substance according to any precedingclaim wherein R¹ when taken alone is OH, CN, halogen, NO₂, NH₂, NY²WY¹or Het¹.
 4. A substance according to any preceding claim wherein R² whentaken alone is H.
 5. A substance according to claim 1 or 2 wherein R¹and R² are taken together with the carbon atoms to which they areattached and represent an optionally benzo-fused 5- to 7-memberedheteroaryl ring optionally substituted by C₁₋₄ alkyl or C₁₋₄ haloalkyl.6. A substance according to any preceding claim wherein X is Cl.
 7. Asubstance according to any preceding claim wherein n is 0 and q is
 0. 8.A substance according to any preceding claim wherein R³ is H, CN, orC₁₋₆ alkyl (optionally substituted by one or more halogen, OH, C₁₋₆alkoxy, C₁₋₆ alkoxycarbonyl, C₂₋₆ alkanoyl, C₂₋₆ alkanoyloxy, C₂₋₆alkyloxycarbonyloxy, NR¹²R¹³, CONR¹²R¹³ and/or NY²WY¹).
 9. A substanceaccording to any preceding claim wherein R⁴ is C₁₋₁₀ alkyl, C₃₋₁₀alkenyl or C₃₋₁₀ alkynyl each of which groups is linked to the N atomvia a sp³ carbon, each of which is optionally substituted by C₃₋₈cycloalkyl, aryl (optionally substituted by one or more methyl, ethyl,halogen, CH₂CN, CF₃, NHSO₂CH₃, OH, ═O, methoxy, OCF₃), optionallybenzo-fused heteroaryl (optionally substituted by one or more methyl,halogen, CH₂CN, CF₃, NHSO₂CH₃, methoxy, OH, ═O, OCF₃), OH, aryloxy(optionally substituted by one or more methyl, halogen, CH₂CN, OH, ═O,CF₃, NHSO₂CH₃, methoxy, OCF₃), CN, CF₃, C₁₋₆ alkoxy, C₃₋₈ cycloalkyloxy,CONH(C₃₋₈ cycloalkyl), adamantyl, or (optionally benzo-fused)heteroaryloxy (optionally substituted by one or more methyl, halogen,CH₂CN, CF₃, NHSO₂CH₃, OH, ═O, methoxy, OCF₃).
 10. A substance accordingto any preceding claim wherein R⁵, R⁶, R⁷, R⁸ R⁹ and R¹⁰ are each takenseparately and are all H.
 11. A substance according to any precedingclaim wherein the “Ar” ring represents a group of formula:


12. A substance according to any preceding claim wherein R³ is H, CH₃,C₂H₅, i-C₃H₇, n-C₃H₇ or CH₂OCH₃.
 13. A substance according to anypreceding claim except claim 5 wherein R¹ is OH, CN, I, Cl, NH₂, NO₂,optionally benzo-fused heteroaryl, NHSO₂Y¹, NHCOY¹ or NHCO₂Y¹.
 14. Asubstance according to any preceding claim wherein R⁴ is n-hexyl,3-phenylpropyl, 3-phenyloxypropyl, 3-cyclohexylpropyl, 5-methylhexyl,2-phenyloxyethyl, (4-cyanomethyl)benzyl, 2-cyclohexyloxyethyl,2-benzyloxyethyl, 3-cyclohexylprop-2-en-1-yl,2-(cyclohexylcarbonyl)ethyl, 3-(2-methylphenyl)propyl,3-phenylprop-2-en-1-yl, 2-(indol-3-yl)ethyl,3-cyclohexyl-3-hydroxypropyl, (indan-2-yl)methyl,3-(4-fluorophenyl)propyl, 3-(thien-2-yl)propyl, 3-(thien-3-yl)propyl,3-(pyrid-2-yl)propyl, 3-(3-methylthien-2-yl)propyl,3-(thien-2-yl)prop-2-en-1-yl, 3-(thien-3-yl)prop-2-en-1-yl,3-(pyrid-2-yl)prop-2-en-1-yl, 3-(3-methylthien-2-yl)prop-2-en-1-yl,3-(3-methylpyrid-2-yl)prop-2-en-1-yl or 3-(2-methoxyphenyl)propyl.
 15. Asubstance according to any preceding claim except claims 3, 4 and 13wherein R¹ and R² are taken together with the carbon atoms to which theyare attached are a 5-membered heteroaryl moiety optionally substitutedby C₁₋₄ alkyl or C₁₋₄ haloalkyl.
 16. A substance according to anypreceding claim wherein R³ is CH₃ or C₂H₅.
 17. A substance according toany preceding claim except claims 5 and 15 wherein R¹ when taken aloneis OH, CN, I, Cl, NH₂, NO₂, 1,2,3-triazolyl, 1,2,4-triazolyl,imidazol-2-yl, pyridin-2-yl, thien-2-yl, imidazol4-yl,benzimidazol-2-yl, NHSO₂(C₁₋₆ alkyl), NHSO₂(C₁₋₆ alkyl substituted bymethoxy, CONH₂, OH, CO₂(C₂₋₆ alkyl), phthalimido, NH₂ or halogen),NHSO₂NH₂, NHSO₂NH(C₁₋₆ alkyl), NHSO₂N(C₁₋₆ alkyl)₂, NHSO₂Het_(1a),NHCO(C₁₋₆ alkyl) or NHCO₂(C₁₋₆ alkyl).
 18. A substance according toclaim 17 wherein R¹ is OH, NHSO₂CH₃, NHSO₂C₂H₅, NHSO₂(n-C₃H₇),NHSO₂(i-C₃H₇), NHSO₂(n-C₄H₇), NHSO₂NH(i-C₃H₇),NHSO₂(N-methylimidazol-4-yl), NHSO₂(CH₂)₂OCH₃, NHSO₂(CH₂)₂OH,1,2,4-triazolyl or imidazol-2-yl.
 19. A substance according to claim 18wherein R¹ is OH, NHSO₂CH₃, NHSO₂C₂H₅ or imidazol-2-yl.
 20. A substanceaccording to claim 15 wherein R¹ and R² when taken together with thecarbon atoms to which they are attached are an imidazole groupoptionally 2-substituted by CF₃.
 21. A substance according to anypreceding claim wherein R⁴ is n-hexyl, 3-phenylpropyl,(4-cyanomethyl)benzyl, 2-benzyloxyethyl, 3-cyclohexylprop-2-en-1-yl,2-(indol-3-yl)ethyl, 3-(2-methylphenyl)propyl, 3-(4-fluorophenyl)propyl,3-(pyrid-2-yl)propyl, 3-phenylprop-2-en-1-yl,3-cyclohexyl-3-hydroxypropyl, 3-(thien-2-yl)propyl,3-(thien-3-yl)propyl, 3-(3-methylthien-2-yl)propyl,3-(thien-2-yl)prop-2-en-1-yl, 3-(thien-3-yl)prop-2-en-1-yl,3-(pyrid-2-yl)prop-2-en-1-yl, 3-(3-methylthien-2-yl)prop-2-en-1-yl,3-(6-methylpyrid-2-yl)prop-2-en-1-yl or 3-(2-methoxyphenyl)propyl.
 22. Asubstance according to claim 1 which has the following relativestereochemistry:


23. A substance according to claim 1 which is selected from thecompounds of the Examples as described herein, and the salts andprodrugs thereof.
 24. A substance according to claim 23 selected fromthe compounds of the Examples 1, 5, 6, 10-13, 18, 20, 25-28, 32-34, 36,38, 40, 42, 45, 47, 48, 57, 62, 67-69, 76, 79, 80, 84, 88, 90, 92, 97,99, 102, 113, 114, 118, 119, 122-124, 136, 139 and 143, and the saltsand prodrugs thereof.
 25. A substance according to claim 24 selectedfrom the compounds of the Examples 1, 5, 10, 12, 13, 26, 28, 36, 40, 45,47, 48, 62, 68, 69, 79, 80, 84, 88, 90, 97, 99, 102, 113, 118, 114, 119,122-124, 136, 139 and 143 described herein and the salts and prodrugsthereof.
 26. A substance according to claim 25 selected from thecompounds of the Examples 1, 10, 13, 26, 28, 62, 68, 69, 79, 80, 84, 88,90, 97, 102, 113, 114, 118, 119, 12, 123, 124, 136, 139, and 143described herein and the salts and prodrugs thereof.
 27. A substanceaccording to claim 26 selected from the compounds of the Examples 1, 10,26, 79, 97, 102, 118, 139 and 143 described herein and the salts andprodrugs thereof.
 28. A pharmaceutical or veterinary compositioncomprising a substance according to any one of the preceding claims, anda pharmaceutically or veterinarily acceptable carrier.
 29. A substanceaccording to any of claims 1 to 27 for use in medicine.
 30. The use of asubstance according to any one of claims 1 to 27 in the manufacture of amedicament for the treatment of a disease or condition mediated byopiate receptors.
 31. A method of treatment of a condition mediated byan opiate receptor or receptors comprising administration of atherapeutically active amount of a substance according to any one ofclaims 1 to
 27. 32. A process for the preparation of a substanceaccording to claim 1 which comprises: (a) for compounds of formula I inwhich q is 0 and R¹ represents NY²WY¹, reacting a compound of formulaII,

 with a compound of formula III, Z¹—WY¹  IIIwherein Z¹ is a suitableleaving group, such as halogen or Y¹SO₂O—; (b) for compounds of formulaI in which q is 0 and R⁶ and R⁷ both represent H, reduction of acompound of formula IV,

 using a suitable reducing agent; (c) for compounds of formula I inwhich q is 0 and R⁹ and R¹⁰ both represent H, reduction of a compound offormula V,

 using a suitable reducing agent; (d) for compounds of formula I inwhich q is 0 and R¹ and R² are attached to adjacent carbon atoms and aretaken together with the carbon atoms to which they are attached torepresent Het^(1a), in which Het^(1a) represents an imidazolo unit,reaction of a corresponding compound of formula VI,

 with a compound of formula VII, R^(y)CO₂H  VIIwherein R^(y) representsH or any of the optional substituents on Het^(1a) (as defined above),preferably H, C₁₋₄ alkyl or C₁₋₄ haloalkyl; (e) where q is 0, reacting acompound of formula VIII,

 with a compound of formula IX, R⁴—Lg  IXwherein Lg is a leaving group;(f) for compounds of formula I in which q is 0 and R⁶, R⁷, R⁹ and R¹⁰are all H, reduction of a compound of formula X,

 with a suitable reducing agent; (g) for compounds of formula I in whichq is 0 and R¹ represents OH, reacting a compound of formula II, where Y²is H, as defined above, with fluoroboric acid and isoamyl nitrite; (h)for compounds of formula I in which q is 0 and R¹ represents Cl,reacting a compound of formula II, where Y² is H, as defined above, withsodium nitrite in the presence of dilute acid, followed by reaction withcopper (I) chloride in the presence of concentrated acid; (i) forcompounds of formula I in which q is 1, reacting a compound of formula Iwhere q is 0 with a suitable oxidising agent such as aqueous hydrogenperoxide; or (j) for compounds of formula I where q is 0, by reductionof a corresponding compound of formula XXXI,

where R^(4a)CH₂ takes the same meaning as R⁴ as defined above, and wheredesired or necessary converting the resulting compound of formula I intoa pharmaceutically or veterinarily acceptable derivative or vice versa.32. A compound of formula II, IV, V, VI, VIII, X, X^(a), XI, XII, XIII,XIV, XXI, XXII, XXIII, XXIV, XXV, XXIX, XXIXa, XXX, XXXI as describedherein.